VCV000009325.130 - ClinVar

NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

76 submissions

72 submitters

14 conditions

Reviewed by expert panel

Pathogenic

Jun 2024 by ClinGen ENIGMA… FDA Recognized Database

for BRCA2-related cancer predisposition

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)

Variation ID: 9325 Accession: VCV000009325.130

Type and length

Deletion, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340301 (GRCh38) [ NCBI UCSC ] 13: 32914438 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 12, 2013	Oct 20, 2024	Jun 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.5946del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ser1982fs	frameshift
NM_000059.3:c.5946delT
NC_000013.11:g.32340301del
NC_000013.10:g.32914438del
NG_012772.3:g.29822del
LRG_293:g.29822del
U43746.1:n.6174delT

... more HGVS ... less HGVS

Protein change

S1982fs

Other names

NP_000050.3:p.Ser1982ArgfsTer22
NM_000059.4(BRCA2):c.5946del
6174delT

Canonical SPDI

NC_000013.11:32340300:T:

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00011

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00016

The Genome Aggregation Database (gnomAD) 0.00019

Exome Aggregation Consortium (ExAC) 0.00027

The Genome Aggregation Database (gnomAD), exomes 0.00029

Links

Breast Cancer Information Core (BIC) (BRCA2): 6174&base_change=del T ClinGen: CA023403 Genetic Testing Registry (GTR): GTR000530707 Genetic Testing Registry (GTR): GTR000560788 Genetic Testing Registry (GTR): GTR000566692 OMIM: 600185.0005 OMIM: 600185.0009 dbSNP: rs80359550 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BRCA2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	18969	19128

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Pancreatic cancer, susceptibility to, 2	risk factor (1)	no assertion criteria provided	Sep 12, 2016	RCV000009911.13
Fanconi anemia complementation group D1	Pathogenic (1)	no assertion criteria provided	Sep 12, 2016	RCV000009912.13
Breast-ovarian cancer, familial, susceptibility to, 2	Pathogenic (28)	criteria provided, multiple submitters, no conflicts	Jul 4, 2024	RCV000009910.47
Hereditary breast ovarian cancer syndrome	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000034451.45
Familial cancer of breast	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 6, 2024	RCV000044800.23
Hereditary cancer-predisposing syndrome	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Mar 6, 2023	RCV000129627.23
BRCA2-related disorder	Pathogenic (2)	criteria provided, single submitter	Apr 28, 2017	RCV000367838.14
not provided	Pathogenic (19)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000212245.71
Breast neoplasm	Pathogenic (1)	criteria provided, single submitter	-	RCV000414179.9
Breast and/or ovarian cancer	Pathogenic (1)	criteria provided, single submitter	Mar 6, 2022	RCV000768632.11
Ovarian neoplasm	Pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785226.10
Fanconi anemia complementation group D1 Hereditary breast ovarian cancer syndrome	not provided (1)	no classification provided	-	RCV001535431.10
Endometrial carcinoma	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128125.8
BRCA2-related cancer predisposition	Pathogenic (1)	reviewed by expert panel	Jun 11, 2024	RCV004566711.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jun 11, 2024)	reviewed by expert panel (CSpec BRCA1/2ACMG Rules Specifications V1.0) Method: curation	BRCA2-related cancer predisposition (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004101432.2 First in ClinVar: Nov 11, 2023 Last updated: Jun 17, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8c8c6973-0686-4b0b-afb5-db5e988a2e83 Comment: The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at … (more) The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis <=5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). (less)
Pathogenic (-)	criteria provided, single submitter (Silva et al. (BMC Med Genet. 2014)) Method: research	Breast Cancer Affected status: yes Allele origin: germline	A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center Accession: SCV000492446.1 First in ClinVar: Jan 09, 2017 Last updated: Jan 09, 2017	Publications: PubMed (2) PubMed: 23469205‚ 24884479
Pathogenic (May 16, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	{Breast-ovarian cancer, familial, 2} Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000593749.1 First in ClinVar: Jul 27, 2017 Last updated: Jul 27, 2017
Pathogenic (Jul 12, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV000679720.1 First in ClinVar: Oct 21, 2017 Last updated: Oct 21, 2017
Pathogenic (Sep 21, 2015)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744479.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Nov 07, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: no Allele origin: unknown	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Study: Clinvar_gadteam_Clinical_exome_analysis_3 Accession: SCV000803796.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (May 24, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839905.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Comment: The c.5946del (p.Ser1982Argfs22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, … (more) The c.5946del (p.Ser1982Argfs22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.[leduc, 2017-03-07] (less)
Pathogenic (Feb 03, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225181.5 First in ClinVar: Jun 28, 2015 Last updated: Sep 28, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 Number of individuals with the variant: 5 Sex: mixed
Pathogenic (Aug 14, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cancer Syndrome, Hereditary Affected status: yes Allele origin: germline	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego Accession: SCV000996186.1 First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019	Comment: This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) … (more) This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (May 01, 2019)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918979.2 First in ClinVar: Jun 03, 2019 Last updated: Nov 10, 2019	Publications: PubMed (4) PubMed: 15695382‚ 9758598‚ 22430266‚ 9042909 Comment: Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0002765 in 282088 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503) and was predominantly observed in the Ashkenazi Jewish subpopulation. This variant is a well-established Ashkenazi Jewish founder mutation. The variant, c.5946delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Abeliovich_1997, Friedman_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). Multiple ClinVar submissions after 2014 cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934380.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (Nov 16, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State Accession: SCV002025788.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: DOI: 10.3389/fgene.2022.834265 DOI: 10.3389/fgene.2022.834265 Number of individuals with the variant: 1 Geographic origin: South Africa Testing laboratory: National Health Laboratory Service (NHLS)
Pathogenic (Oct 23, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002536189.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The BRCA2 c.5946delT (p.S1982RfsX22) variant is a well characterized pathogenic variant that has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (PMID: … (more) The BRCA2 c.5946delT (p.S1982RfsX22) variant is a well characterized pathogenic variant that has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (PMID: 9042909). This variant is also known as 6174delT in the literature. This variant is a founder pathogenic variant in the Ashkenazi Jewish population (PMID: 9042909, 9150153) and it has been reported in individuals of other ethnicities as well (PMID: 8758903, 10417300). This variant causes a frameshift at amino acid 1982 that results in premature termination 22 amino acids downstream. This variant is expected to result in an absent or non-functional protein product (loss of function). Loss of function variants in BRCA2 are known to be pathogenic (PMID: 29446198). This variant was observed in 61/10364 chromosomes in the Ashkenazi Jewish subpopulation, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 9325). Based on the current evidence available, this variant was interpreted as pathogenic. (less)	Publications: PubMed (5) PubMed: 9042909‚ 9150153‚ 8758903‚ 10417300‚ 29446198
Pathogenic (Aug 02, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581177.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4	Number of individuals with the variant: 2 Sex: female
Pathogenic (Oct 02, 2015)	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge Accession: SCV000327312.4 First in ClinVar: Jun 24, 2016 Last updated: Dec 11, 2022
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hereditary breast and ovarian cancer syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838826.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Apr 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761748.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	New York Genome Center Accession: SCV002764549.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Publications: PubMed (5) PubMed: 20301425‚ 29084914‚ 29433453‚ 29321669‚ 28767289 Comment: The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant … (more) The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 29321669, 28767289). Based on the available evidence, the c.5946delT, p.Ser1982ArgfsTer22 variant is classified as pathogenic. (less) Observation 1: Clinical Features: Hyperlipidemia (present) , Diabetes mellitus (present) Secondary finding: yes Observation 2: Clinical Features: Hyperlipidemia (present) , Hepatic steatosis (present) Secondary finding: yes
Pathogenic (Mar 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000219371.5 First in ClinVar: Mar 29, 2015 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010347.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 19, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000296747.7 First in ClinVar: Jun 24, 2016 Last updated: Jan 06, 2024	Publications: PubMed (75): PubMed: 26295337 21324516 25980754 23341105 22006311 20887823 26681312 28767289 26440929 29907814 19530235 14559878 26064523 16825431 30883245 10464624 10733239 10739756 19188187 20736950 22009639 22430266 22703879 23633455 23658460 26556299 26689913 27425403 27836010 27989354 29084914 29161300 29321669 29339979 29368341 29433453 29439820 29506128 29625052 29937315 29961768 29978187 30113427 30122538 30152102 30186769 30274973 30322717 30489631 30613976 30620386 30702160 30716324 30720243 30787465 31263054 31444830 31447099 31589614 31948886 32338768 32341426 32719484 32853339 32885271 33077847 33087929 34308366 34399810 8673091 17591843 8841191 15695382 23199084 20104584 Comment: This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this … (more) This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (14/128890 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a BRCA2 founder variant in the Ashkenazi Jewish population with a carrier frequency of approximately 1.52% (PMID: 17591843 (2007) and 8841191 (1996)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Nov 16, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019064.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Mar 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000292121.5 First in ClinVar: Jul 08, 2016 Last updated: Feb 14, 2024	Publications: PubMed (21) PubMed: 8524414‚ 8673091‚ 8673092‚ 8758903‚ 8841191‚ 8898735‚ 9145676‚ 12473589‚ 14576434‚ 15695382‚ 15994883‚ 18607349‚ 20104584‚ 21324516‚ 22006311‚ 22430266‚ 28944232‚ 29084914‚ 29433453‚ 30152102‚ 33471991 Comment: This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is also … (more) This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 6174delT in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair and other ancillary assays (PMID: 15695382, 18607349). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.6-1.52% minor allele frequency (PMID: 8673092, 30152102). This variant has been reported in dozens of individuals affected with breast and/or ovarian cancer in Ashkenazi Jewish and in non-Ashkenazi Jewish populations (PMID: 8524414, 8673091, 8673092, 8758903, 8898735, 8841191, 9145676, 12473589, 14576434, 20104584, 21324516, 22006311, 22430266, 28944232, 29084914, 29433453). This variant has been reported with cosegregation likelihood ratio for pathogenicity of over 1,000 (PMID: 15695382) and in a breast cancer case-control meta-analysis in 26/60440 cases and 8/53453 unaffected individuals with OR 2.874 (95%CI 1.301 to 6.349) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000149). The risk of female breast cancer among carriers of this mutation is 43-55% by age 70, and the risk of ovarian cancer is 18-37% by age 70 (PMID: 9145676, 15994883, 22430266). This variant has been identified in 78/282088 chromosomes in the general population (61/10364 Ashkenazi Jewish chromosomes) by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000072813.17 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 20104584‚ 8758903‚ 9042909‚ 10417300‚ 15994883‚ 22430266 Comment: This sequence change creates a premature translational stop signal (p.Ser1982Argfs22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Ser1982Argfs22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359550, gnomAD 0.6%). This premature translational stop signal has been observed in individual(s) with breast (43% to 55% lifetime risk) and/or ovarian cancer (20% to 37% lifetime risk) (PMID: 8758903, 9042909, 10417300, 15994883, 22430266). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8758903, 9042909, 10417300, 22430266). This premature translational stop signal has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. This variant is also known as 6174delT. ClinVar contains an entry for this variant (Variation ID: 9325). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 27, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000602754.8 First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024	Comment: The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (rs80359550), also published as 6174delT, is reported as a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch … (more) The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (rs80359550), also published as 6174delT, is reported as a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch 1996, Finkelman 2012), and has been associated with hereditary breast and ovarian cancer syndrome. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 9325) and is found in the Ashkenazi Jewish population with an allele frequency of 0.6% (61/10,364 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. [Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. PMID: 9042909. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. PMID: 8673091. Finkelman BS et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol. 2012 Apr 20;30(12):1321-8. PMID: 22430266. (less)
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846675.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: The c.5946del (p.Ser1982Argfs22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, … (more) The c.5946del (p.Ser1982Argfs22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is classified as pathogenic and considered medically actionable. [leduc, 2017-03-07] The c.5946del (p.Ser1982Argfs22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic. (less) Number of individuals with the variant: 75
Pathogenic (Jun 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000605785.4 First in ClinVar: Aug 27, 2017 Last updated: Apr 20, 2024	Publications: PubMed (3) PubMed: 22430266‚ 8673091‚ 26867194 Comment: The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012 PMID: 22430266) and has been identified in >500 individuals … (more) The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012 PMID: 22430266) and has been identified in >500 individuals of various ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/projects/bic/). It has also been identified in 0.6% (20/3466) of Ashkenazi Jewish and 0.009% (6/68002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1982 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function BRCA2 is an established disease mechanism for hereditary breast and ovarian cancer (HBOC) syndrome. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar variation ID 9325). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Strong. (less)
Pathogenic (Jan 13, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000184420.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 19188187‚ 22006311‚ 22009639‚ 22430266‚ 22703879‚ 23633455‚ 23658460‚ 26440929‚ 26681312 Comment: The c.5946delT (p.S1982Rfs22) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 5946, … (more) The c.5946delT (p.S1982Rfs22) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon after 22 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.028% (78/282088) total alleles studied. The highest observed frequency was 0.589% (61/10364) of Ashkenazi Jewish alleles. This variant is one of the well-described Ashkenazi Jewish founder mutations and has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu, 2009; Walsh, 2011; Johnston, 2012; Bayraktar, 2012; George, 2013; Lucas, 2013; Salo-Mullen, 2015; Susswein, 2016). Another study indicated that carriers of the c.5946delT variant may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 likely pathogenic/pathogenic variants (Finkelman, 2012). This variant is also designated as 6174delT in published literature. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (May 27, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005045989.1 First in ClinVar: Jun 02, 2024 Last updated: Jun 02, 2024	Comment: PM3_Strong; PVS1; PM5_PTC_Strong
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550357.7 First in ClinVar: Jul 23, 2022 Last updated: Aug 04, 2024
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199797.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (May 06, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368163.1 First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM5_STR Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Nov 03, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Michigan Medical Genetics Laboratories, University of Michigan Accession: SCV000195993.1 First in ClinVar: Feb 26, 2016 Last updated: Feb 26, 2016	Tissue: Blood
Pathogenic (Feb 12, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000575747.1 First in ClinVar: Jun 24, 2016 Last updated: Jun 24, 2016
Pathogenic (Sep 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Gharavi Laboratory, Columbia University Accession: SCV000809465.1 First in ClinVar: Sep 28, 2017 Last updated: Sep 28, 2017
Pathogenic (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	BRCA2-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383728.3 First in ClinVar: Dec 06, 2016 Last updated: May 27, 2019	Publications: PubMed (14) PubMed: 14559878‚ 8673092‚ 8673091‚ 12473589‚ 18607349‚ 8841191‚ 20216074‚ 9145676‚ 15695382‚ 8841192‚ 10570174‚ 22430266‚ 16825431‚ 14576434 Comment: The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a … (more) The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a well-described founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, with a carrier frequency of ~1.5% (Roa et al. 1996; Neuhausen et al. 1996). The variant has been shown to occur in approximately eight percent of women diagnosed with breast cancer before the age of 42 years (Neuhausen et al. 1996; Oddoux et al. 1996; Petrucelli et al. 2010; Finkelman et al. 2012). By the age of 70, 43% of individuals who carry this variant are predicted to develop breast cancer and 20% are predicted to develop ovarian cancer (Struewing et al. 1997; King et al. 2003). Across a selection of the literature, the p.Ser1982ArgfsTer22 variant has been identified in 55 of 1,272 (4%) individuals with breast cancer, 44 of 382 (11.5%) individuals with ovarian cancer, and at least 118 of 9,658 (1.2%) Ashkenazi Jewish individuals from the general population (Couch et al. 1996; Roa et al. 1996; Neuhausen et al. 1996; Oddoux et al. 1996; Struewing et al. 1997; Satagopan et al. 2002; King et al. 2003). Additionally, the p.Ser1982ArgfsTer22 variant has been identified in a compound heterozygous state in four individuals, including two cousins, with Fanconi anemia and brain tumors from three different Ashkenazi Jewish families (Offit et al. 2003; Alter et al. 2007). The p.Ser1982ArgfsTer22 variant was absent from at least 1,726 non-Ashkenazi Jewish controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated decreased cell viability and survival in carriers of the p.Ser1982ArgfsTer22 variant (Wu et al. 2005). The variant protein was shown to be localized in the cytoplasm and not in the nucleus. The p.Ser1982ArgfsTer22 variant is predicted to result in truncation of approximately 41% of the BRCA2 protein, which would remove two signals required for nuclear localization and represents a likely mode of pathogenicity for the variant (Spain et al. 1999). In a study in mouse embryonic stem cells, the p.Ser1982ArgfsTer22 variant failed to rescue the loss of endogenous BRCA2 (Kuznetsov et al. 2008). Based on the collective evidence, the p.Ser1982ArgfsTer22 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	GeneKor MSA Accession: SCV000693574.2 First in ClinVar: Sep 28, 2017 Last updated: May 04, 2020	Comment: This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid … (more) This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid residues. The protein product thus produced is truncated and non-functional. Truncating variants in BRCA2 are known to be pathogenic. In the literature, this variant is also known as 6174delT and is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266). Moreover, it has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883). The mutation database ClinVar contains entries for this variant (Variation ID: 9325). (less)
Pathogenic (Aug 07, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450241.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 17
Pathogenic (Dec 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: no Allele origin: germline	Department of Pediatrics, Memorial Sloan Kettering Cancer Center Accession: SCV001478111.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Publications: PubMed (1) PubMed: 28873162
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762173.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Neoplasm of the pancreas (present) Sex: male
Pathogenic (May 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV002570374.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (7) PubMed: 14559878‚ 15695382‚ 16825431‚ 20301425‚ 29084914‚ 30152102‚ 8758903 Comment: This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or … (more) This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or recessive manner. It is known as a founder mutation in the Ashkenazi Jewish population and has also been observed in individuals of non-Ashkenazi Jewish descent. It is rare (<0.1%) in a large population dataset (gnomAD: 78/282088 total alleles; 0.0277%; no homozygotes) and has been reported in ClinVar(Variation ID 9325). This frameshift variant results in a premature stop codon in exon 11, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider this variant to be pathogenic. (less)
Pathogenic (Jul 01, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Department of Medical Genetics, Oslo University Hospital Accession: SCV000605651.3 First in ClinVar: Jul 27, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 11
Pathogenic (Mar 22, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002526014.2 First in ClinVar: Jun 18, 2022 Last updated: Dec 24, 2022	Comment: The BRCA2 c.5946del (p.Ser1982ArgfsTer22) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or … (more) The BRCA2 c.5946del (p.Ser1982ArgfsTer22) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.59% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/13-32914437-GT-G?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 8673092, 9042909, 9150153, 15994883, 22430266, 30152102). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 6174delT in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. (less)
Pathogenic (Apr 07, 2014)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: literature only	Breast-ovarian cancer, familial 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000154098.2 First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022	Publications: PubMed (15) PubMed: 15695382‚ 22006311‚ 22009639‚ 20887823‚ 19188187‚ 22703879‚ 23658460‚ 8673092‚ 15994883‚ 8673091‚ 21324516‚ 22430266‚ 9145676‚ 10570174‚ 18607349
Pathogenic (Jun 11, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000108631.16 First in ClinVar: Dec 10, 2013 Last updated: Mar 04, 2023	Comment: Common founder variant in the Ashkenazi Jewish population (Oddoux 1996); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more) Common founder variant in the Ashkenazi Jewish population (Oddoux 1996); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: increased sensitivity to MMC, decreased HDR, and increased centrosome amplification compared to wild-type (Wu 2005); Observed in approximately 1% of the Ashkenazi Jewish population (Oddoux 1996); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6174delT; This variant is associated with the following publications: (PMID: 20736950, 20887823, 28049106, 28291774, 30620386, 27836010, 23633455, 15695382, 19188187, 22703879, 22009639, 22430266, 23658460, 23341105, 22006311, 21324516, 8673091, 25980754, 26440929, 27425403, 14559878, 26681312, 29321669, 29339979, 29433453, 29368341, 29084914, 27989354, 29907814, 26556299, 10464624, 28767289, 8841192, 29161300, 29439820, 30274973, 30152102, 29506128, 30122538, 30716324, 30186769, 30720243, 29961768, 30702160, 29978187, 30322717, 29937315, 30113427, 30489631, 31263054, 31444830, 32438681, 31512090, 29625052, 26689913, 31447099, 31948886, 34308366, 10739756, 10733239, 34399810, 33077847, 31589614, 32853339, 32341426, 32719484, 32885271, 32338768, 30787465, 30613976, 33087929) (less)
Pathogenic (Mar 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center Accession: SCV004037369.1 First in ClinVar: Sep 30, 2023 Last updated: Sep 30, 2023	Age: 60-69 years Sex: female Tissue: peripheral blood Secondary finding: yes
Pathogenic (Jul 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004041350.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Oct 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: no Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004042779.1 First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023	Comment: ACMG criteria used to clasify this variant:PVS1, PS4 Clinical Features: Family history of cancer (present) Indication for testing: Family history of cancer
Pathogenic (Jun 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778694.4 First in ClinVar: Sep 28, 2017 Last updated: Jan 26, 2024	Comment: PP5, PS4_moderate, PVS1 Number of individuals with the variant: 11
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV000540997.2 First in ClinVar: Dec 17, 2016 Last updated: Jun 17, 2024
Pathogenic (Jul 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005073662.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024	Clinical Features: Breast carcinoma (present)
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001501475.21 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Comment: BRCA2: PVS1, PS4:Moderate, PM2:Supporting Number of individuals with the variant: 11
pathogenic (Jul 13, 2012)	no assertion criteria provided Method: research	Breast-ovarian cancer, familial Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043218.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Pathogenic. Observation 1: Number of individuals with the variant: 1 Age: 50-59 years Sex: male Ethnicity/Population group: Ashkenazi Jewish Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less) Observation 2: Number of individuals with the variant: 1 Age: 60-69 years Sex: male Ethnicity/Population group: Ashkenazi Jewish Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less) Observation 3: Number of individuals with the variant: 1 Age: 50-59 years Sex: male Ethnicity/Population group: Ashkenazi Jewish Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Pathogenic (Dec 21, 1995)	no assertion criteria provided Method: literature only	BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000030127.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 26, 2015	Publications: PubMed (2) PubMed: 8524414‚ 8075631 Comment on evidence: In 2 families from Montreal with breast-ovarian cancer (BROVCA2; 612555), Wooster et al. (1995) found a T deletion and an AAAC deletion (600185.0006), respectively, in … (more) In 2 families from Montreal with breast-ovarian cancer (BROVCA2; 612555), Wooster et al. (1995) found a T deletion and an AAAC deletion (600185.0006), respectively, in the BRCA2 gene. Both of these families included a male breast cancer case; previous analyses had indicated that the large majority of such families have BRCA2 mutations (Stratton et al., 1994). (less)
Pathogenic (Jun 10, 2015)	no assertion criteria provided Method: research	Breast-ovarian cancer, familial, susceptibility to, 2 (Autosomal dominant inheritance) Affected status: not applicable Allele origin: not applicable	Centro de Genética y Biología Molecular, Universidad de San Martín de Porres Study: Mutational analysis of BRCA1 and BRCA2 genes in peruvian families with hereditary breast and ovarian cancer Accession: SCV000263344.1 First in ClinVar: Feb 26, 2016 Last updated: Feb 26, 2016	Sex: female Tissue: Blood Comment on evidence: Phatogenic mutation
Pathogenic (Jan 15, 2013)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: not provided Allele origin: germline	Sharing Clinical Reports Project (SCRP) Accession: SCV000054198.6 First in ClinVar: Apr 04, 2013 Last updated: Jun 24, 2016
risk factor (Sep 12, 2016)	no assertion criteria provided Method: literature only	PANCREATIC CANCER, SUSCEPTIBILITY TO, 2 Affected status: not provided Allele origin: not provided	OMIM Accession: SCV000030132.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2016
Pathogenic (Sep 12, 2016)	no assertion criteria provided Method: literature only	FANCONI ANEMIA, COMPLEMENTATION GROUP D1 Affected status: not provided Allele origin: not provided	OMIM Accession: SCV000030133.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 16, 2016
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000484936.1 First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798609.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906091.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (Jul 17, 2024)	no assertion criteria provided Method: clinical testing	BRCA2-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805732.2 First in ClinVar: Sep 28, 2017 Last updated: Oct 08, 2024	Comment: The BRCA2 c.5946delT variant is predicted to result in a frameshift and premature protein termination (p.Ser1982Argfs22). This variant, also described as 6174delT in the literature, … (more) The BRCA2 c.5946delT variant is predicted to result in a frameshift and premature protein termination (p.Ser1982Argfs22). This variant, also described as 6174delT in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #612555; Couch et al. 1996. PubMed ID: 8673091). It has also been associated with autosomal recessive Fanconi anemia, complementation group D1 (OMIM #605724; Offit et al. 2003. PubMed ID: 14559878). This is a founder variant in the Ashkenazi Jewish population, identified in about 1.5% of Ashkenazi Jewish individuals unselected for breast cancer (Abeliovich et al. 1997. PubMed ID: 9042909; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomAD. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/). In summary, this variant is interpreted as pathogenic. (less)
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189906.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (4) PubMed: 20301425‚ 23199084‚ 15994883‚ 22430266
Pathogenic (Aug 01, 2015)	no assertion criteria provided Method: research	BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer Affected status: no Allele origin: germline	Curoverse Accession: SCV000245334.1 First in ClinVar: Aug 31, 2015 Last updated: Aug 31, 2015	Publications: pmc: 3583621 pmc: 3583621 DOI: 10.1001/jama.2011.678 DOI: 10.1001/jama.2011.678 Other databases http://www.ncbi.nlm.nih.gov/pmc/… http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583621/ http://jama.jamanetwork.com/arti… http://jama.jamanetwork.com/article.aspx?articleid=2214084 Comment: Frameshifts in BRCA2 are considered pathogenic, and this is a BRCA2 Ser1982Arg frameshift variant in exon 11 Number of individuals with the variant: 1 Age: 40-49 years Sex: male
Pathogenic (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline, unknown	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000146737.2 First in ClinVar: Apr 01, 2014 Last updated: Oct 11, 2015	Observation 1: Number of individuals with the variant: 185 Observation 2: Number of individuals with the variant: 69 Geographic origin: Ashkenazi Observation 3: Number of individuals with the variant: 1 Geographic origin: Ashkenazi, Western European Observation 4: Number of individuals with the variant: 1 Geographic origin: Ashkenazi, Western, Central/Eastern European Observation 5: Number of individuals with the variant: 2 Geographic origin: Austria Observation 6: Number of individuals with the variant: 1 Geographic origin: Canada Observation 7: Number of individuals with the variant: 2 Geographic origin: Central/Eastern European Observation 8: Number of individuals with the variant: 2 Geographic origin: Netherlands Observation 9: Number of individuals with the variant: 1 Geographic origin: German French Observation 10: Number of individuals with the variant: 1 Geographic origin: Russia Observation 11: Number of individuals with the variant: 4 Geographic origin: Western European Observation 12: Number of individuals with the variant: 694 Ethnicity/Population group: Ashkenazi Observation 13: Number of individuals with the variant: 6 Ethnicity/Population group: Ashkenazi Geographic origin: American Observation 14: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi Jewish Geographic origin: Canada Observation 15: Number of individuals with the variant: 19 Ethnicity/Population group: Ashkenazi, Central/Eastern European Observation 16: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Central/Eastern European, Italian Observation 17: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Central/Eastern European, Russian Observation 18: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Latin American, Caribbean Observation 19: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Latin American, Caribbean, Mex Observation 20: Number of individuals with the variant: 2 Ethnicity/Population group: Ashkenazi, Western European Observation 21: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Western, Eastern, Central European Observation 22: Number of individuals with the variant: 1 Ethnicity/Population group: Asian Observation 23: Number of individuals with the variant: 1 Ethnicity/Population group: Cacasian Observation 24: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Observation 25: Number of individuals with the variant: 2 Ethnicity/Population group: Caucasian Geographic origin: Netherlands Observation 26: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Italy Observation 27: Number of individuals with the variant: 3 Ethnicity/Population group: Caucasian Non Hispanic Observation 28: Number of individuals with the variant: 12 Ethnicity/Population group: Central/Eastern European Observation 29: Number of individuals with the variant: 1 Ethnicity/Population group: Central/Eastern European, Jewish Observation 30: Number of individuals with the variant: 1 Ethnicity/Population group: Central/Eastern European, Russian Polish Observation 31: Number of individuals with the variant: 1 Ethnicity/Population group: Czech, Hungarian, Russian, Jewish Observation 32: Number of individuals with the variant: 1 Ethnicity/Population group: Dutch Observation 33: Number of individuals with the variant: 11 Ethnicity/Population group: Jewish Observation 34: Number of individuals with the variant: 1 Ethnicity/Population group: Jewish Geographic origin: Chile Observation 35: Number of individuals with the variant: 1 Ethnicity/Population group: Jewish Geographic origin: Sweden Observation 36: Number of individuals with the variant: 1 Ethnicity/Population group: Jewish, Polish Observation 37: Number of individuals with the variant: 1 Ethnicity/Population group: Latin American, Caribbean, Western European Observation 38: Number of individuals with the variant: 1 Ethnicity/Population group: Near Eastern Mid East Observation 39: Number of individuals with the variant: 25 Ethnicity/Population group: Western European Observation 40: Number of individuals with the variant: 18 Ethnicity/Population group: Western European, Ashkenazi Observation 41: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Ashkenazi, Central, Eas Observation 42: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Ashkenazi, English Observation 43: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Ashkenazi, French Ca Observation 44: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Ashkenazi, French, Jewish Observation 45: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Ashkenazi, Irish, Italian Observation 46: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Central/Eastern European Observation 47: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, German, Jewish Observation 48: Number of individuals with the variant: 1 Ethnicity/Population group: Western Europeanan, Central/Eastern European Observation 49: Number of individuals with the variant: 6
Pathogenic (Jan 31, 2014)	no assertion criteria provided Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000587812.1 First in ClinVar: Aug 05, 2017 Last updated: Aug 05, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733276.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (Sep 27, 2017)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000787938.1 First in ClinVar: Oct 21, 2017 Last updated: Oct 21, 2017
Pathogenic (Dec 01, 2018)	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: germline	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000923794.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592016.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The BRCA2 p.Ser1982Argfs22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu … (more) The BRCA2 p.Ser1982Argfs22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu 2009, Borg 2010, Couch 2014, Edwards 2010, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359550) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic by 34 submitters including Invitae, GeneDx, Counsyl, ARUP and Ambry Genetics), COGR (3 entries classified as pathogenic), COSMIC (1x confirmed somatic in adenocarcinoma of the pancreas), LOVD 3.0 (110 entries classified as affects function), UMD-LSDB (75 entries classified as causal), BIC Database (1090 entries classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), and the Zhejiang Colon Cancer Database (classified as pathogenic). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in multiple individuals with breast, ovarian or pancreatic cancer. The variant was identified in control databases in 72 of 276978 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Ashkenazi Jewish in 59 of 10150 chromosomes (freq: 0.006), Other in 3 of 6460 chromosomes (freq: 0.0005), European (Non-Finnish) in 10 of 126512 chromosomes (freq: 0.00008); it was not observed in the African, East Asian, European (Finnish), Latino, or South Asian populations. The c.5946delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1982 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. The truncating BRCA2 6174delT Ashkenazi Jewish founder mutation is associated with a breast cancer risk of 70% by age 70 and identified in the vast majority of Ashkenazi Jewish families with a history of breast and ovarian cancer (Pohlreich 2005, Wu 2005). In addition, a functional study using bacterial artificial chromosomes concluded that this mutation could not rescue lethality in BRCA2-deficient mouse embryonic stem cells, supporting its classification as deleterious (Kuznetsov 2008). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. Assessment Date: 2018/03/07. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001926441.1 First in ClinVar: Sep 25, 2021 Last updated: Sep 25, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002037347.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588896.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Endometrial carcinoma Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804351.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
not provided (-)	no classification provided Method: phenotyping only	Hereditary breast ovarian cancer syndrome Fanconi anemia complementation group D1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749320.2 First in ClinVar: Jul 18, 2021 Last updated: Jun 17, 2024	Comment: Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/5/2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are … (more) Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/5/2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Non-Hodgkin lymphoma (present) , Family history of cancer (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2017-11-22 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Family history (present) , Family history of cancer (present) Indication for testing: Presymptomatic\|Family Testing Age: 70-79 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2018-07-05 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000086654.3 First in ClinVar: Oct 01, 2013 Last updated: Oct 01, 2022	Publications: PubMed (5) PubMed: 11466700‚ 11896095‚ 12402332‚ 17591843‚ 30152102 BookShelf: NBK1247 BookShelf: NBK1247 Comment: Founder variant in Ashkenazi Jews; accounts for 95% of pathogenic variants in this population
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Comment:

The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis <=5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong).

Comment:

This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic.

Comment:

Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0002765 in 282088 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503) and was predominantly observed in the Ashkenazi Jewish subpopulation. This variant is a well-established Ashkenazi Jewish founder mutation. The variant, c.5946delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Abeliovich_1997, Friedman_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). Multiple ClinVar submissions after 2014 cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 29321669, 28767289). Based on the available evidence, the c.5946delT, p.Ser1982ArgfsTer22 variant is classified as pathogenic.

Comment:

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (14/128890 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a BRCA2 founder variant in the Ashkenazi Jewish population with a carrier frequency of approximately 1.52% (PMID: 17591843 (2007) and 8841191 (1996)). Based on the available information, this variant is classified as pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 6174delT in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair and other ancillary assays (PMID: 15695382, 18607349). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.6-1.52% minor allele frequency (PMID: 8673092, 30152102). This variant has been reported in dozens of individuals affected with breast and/or ovarian cancer in Ashkenazi Jewish and in non-Ashkenazi Jewish populations (PMID: 8524414, 8673091, 8673092, 8758903, 8898735, 8841191, 9145676, 12473589, 14576434, 20104584, 21324516, 22006311, 22430266, 28944232, 29084914, 29433453). This variant has been reported with cosegregation likelihood ratio for pathogenicity of over 1,000 (PMID: 15695382) and in a breast cancer case-control meta-analysis in 26/60440 cases and 8/53453 unaffected individuals with OR 2.874 (95%CI 1.301 to 6.349) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000149). The risk of female breast cancer among carriers of this mutation is 43-55% by age 70, and the risk of ovarian cancer is 18-37% by age 70 (PMID: 9145676, 15994883, 22430266). This variant has been identified in 78/282088 chromosomes in the general population (61/10364 Ashkenazi Jewish chromosomes) by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Ser1982Argfs*22) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359550, gnomAD 0.6%). This premature translational stop signal has been observed in individual(s) with breast (43% to 55% lifetime risk) and/or ovarian cancer (20% to 37% lifetime risk) (PMID: 8758903, 9042909, 10417300, 15994883, 22430266). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8758903, 9042909, 10417300, 22430266). This premature translational stop signal has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. This variant is also known as 6174delT. ClinVar contains an entry for this variant (Variation ID: 9325). For these reasons, this variant has been classified as Pathogenic.

Comment:

The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (rs80359550), also published as 6174delT, is reported as a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch 1996, Finkelman 2012), and has been associated with hereditary breast and ovarian cancer syndrome. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 9325) and is found in the Ashkenazi Jewish population with an allele frequency of 0.6% (61/10,364 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. PMID: 9042909. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. PMID: 8673091. Finkelman BS et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol. 2012 Apr 20;30(12):1321-8. PMID: 22430266.

Comment:

The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is classified as pathogenic and considered medically actionable. [leduc, 2017-03-07] The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.

Comment:

The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012 PMID: 22430266) and has been identified in >500 individuals of various ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/projects/bic/). It has also been identified in 0.6% (20/3466) of Ashkenazi Jewish and 0.009% (6/68002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1982 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function BRCA2 is an established disease mechanism for hereditary breast and ovarian cancer (HBOC) syndrome. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar variation ID 9325). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Strong.

Comment:

The c.5946delT (p.S1982Rfs*22) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon after 22 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.028% (78/282088) total alleles studied. The highest observed frequency was 0.589% (61/10364) of Ashkenazi Jewish alleles. This variant is one of the well-described Ashkenazi Jewish founder mutations and has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu, 2009; Walsh, 2011; Johnston, 2012; Bayraktar, 2012; George, 2013; Lucas, 2013; Salo-Mullen, 2015; Susswein, 2016). Another study indicated that carriers of the c.5946delT variant may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 likely pathogenic/pathogenic variants (Finkelman, 2012). This variant is also designated as 6174delT in published literature. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a well-described founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, with a carrier frequency of ~1.5% (Roa et al. 1996; Neuhausen et al. 1996). The variant has been shown to occur in approximately eight percent of women diagnosed with breast cancer before the age of 42 years (Neuhausen et al. 1996; Oddoux et al. 1996; Petrucelli et al. 2010; Finkelman et al. 2012). By the age of 70, 43% of individuals who carry this variant are predicted to develop breast cancer and 20% are predicted to develop ovarian cancer (Struewing et al. 1997; King et al. 2003). Across a selection of the literature, the p.Ser1982ArgfsTer22 variant has been identified in 55 of 1,272 (4%) individuals with breast cancer, 44 of 382 (11.5%) individuals with ovarian cancer, and at least 118 of 9,658 (1.2%) Ashkenazi Jewish individuals from the general population (Couch et al. 1996; Roa et al. 1996; Neuhausen et al. 1996; Oddoux et al. 1996; Struewing et al. 1997; Satagopan et al. 2002; King et al. 2003). Additionally, the p.Ser1982ArgfsTer22 variant has been identified in a compound heterozygous state in four individuals, including two cousins, with Fanconi anemia and brain tumors from three different Ashkenazi Jewish families (Offit et al. 2003; Alter et al. 2007). The p.Ser1982ArgfsTer22 variant was absent from at least 1,726 non-Ashkenazi Jewish controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated decreased cell viability and survival in carriers of the p.Ser1982ArgfsTer22 variant (Wu et al. 2005). The variant protein was shown to be localized in the cytoplasm and not in the nucleus. The p.Ser1982ArgfsTer22 variant is predicted to result in truncation of approximately 41% of the BRCA2 protein, which would remove two signals required for nuclear localization and represents a likely mode of pathogenicity for the variant (Spain et al. 1999). In a study in mouse embryonic stem cells, the p.Ser1982ArgfsTer22 variant failed to rescue the loss of endogenous BRCA2 (Kuznetsov et al. 2008). Based on the collective evidence, the p.Ser1982ArgfsTer22 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid residues. The protein product thus produced is truncated and non-functional. Truncating variants in BRCA2 are known to be pathogenic. In the literature, this variant is also known as 6174delT and is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266). Moreover, it has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883). The mutation database ClinVar contains entries for this variant (Variation ID: 9325).

Comment:

This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or recessive manner. It is known as a founder mutation in the Ashkenazi Jewish population and has also been observed in individuals of non-Ashkenazi Jewish descent. It is rare (<0.1%) in a large population dataset (gnomAD: 78/282088 total alleles; 0.0277%; no homozygotes) and has been reported in ClinVar(Variation ID 9325). This frameshift variant results in a premature stop codon in exon 11, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider this variant to be pathogenic.

Comment:

The BRCA2 c.5946del (p.Ser1982ArgfsTer22) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.59% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/13-32914437-GT-G?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 8673092, 9042909, 9150153, 15994883, 22430266, 30152102). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 6174delT in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4.

Comment:

Common founder variant in the Ashkenazi Jewish population (Oddoux 1996); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: increased sensitivity to MMC, decreased HDR, and increased centrosome amplification compared to wild-type (Wu 2005); Observed in approximately 1% of the Ashkenazi Jewish population (Oddoux 1996); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6174delT; This variant is associated with the following publications: (PMID: 20736950, 20887823, 28049106, 28291774, 30620386, 27836010, 23633455, 15695382, 19188187, 22703879, 22009639, 22430266, 23658460, 23341105, 22006311, 21324516, 8673091, 25980754, 26440929, 27425403, 14559878, 26681312, 29321669, 29339979, 29433453, 29368341, 29084914, 27989354, 29907814, 26556299, 10464624, 28767289, 8841192, 29161300, 29439820, 30274973, 30152102, 29506128, 30122538, 30716324, 30186769, 30720243, 29961768, 30702160, 29978187, 30322717, 29937315, 30113427, 30489631, 31263054, 31444830, 32438681, 31512090, 29625052, 26689913, 31447099, 31948886, 34308366, 10739756, 10733239, 34399810, 33077847, 31589614, 32853339, 32341426, 32719484, 32885271, 32338768, 30787465, 30613976, 33087929)

Comment:

The BRCA2 c.5946delT variant is predicted to result in a frameshift and premature protein termination (p.Ser1982Argfs*22). This variant, also described as 6174delT in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #612555; Couch et al. 1996. PubMed ID: 8673091). It has also been associated with autosomal recessive Fanconi anemia, complementation group D1 (OMIM #605724; Offit et al. 2003. PubMed ID: 14559878). This is a founder variant in the Ashkenazi Jewish population, identified in about 1.5% of Ashkenazi Jewish individuals unselected for breast cancer (Abeliovich et al. 1997. PubMed ID: 9042909; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomAD. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/). In summary, this variant is interpreted as pathogenic.

Comment:

The BRCA2 p.Ser1982Argfs*22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu 2009, Borg 2010, Couch 2014, Edwards 2010, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359550) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, ClinVar (classified as pathogenic by 34 submitters including Invitae, GeneDx, Counsyl, ARUP and Ambry Genetics), COGR (3 entries classified as pathogenic), COSMIC (1x confirmed somatic in adenocarcinoma of the pancreas), LOVD 3.0 (110 entries classified as affects function), UMD-LSDB (75 entries classified as causal), BIC Database (1090 entries classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), and the Zhejiang Colon Cancer Database (classified as pathogenic). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in multiple individuals with breast, ovarian or pancreatic cancer. The variant was identified in control databases in 72 of 276978 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Ashkenazi Jewish in 59 of 10150 chromosomes (freq: 0.006), Other in 3 of 6460 chromosomes (freq: 0.0005), European (Non-Finnish) in 10 of 126512 chromosomes (freq: 0.00008); it was not observed in the African, East Asian, European (Finnish), Latino, or South Asian populations. The c.5946delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1982 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. The truncating BRCA2 6174delT Ashkenazi Jewish founder mutation is associated with a breast cancer risk of 70% by age 70 and identified in the vast majority of Ashkenazi Jewish families with a history of breast and ovarian cancer (Pohlreich 2005, Wu 2005). In addition, a functional study using bacterial artificial chromosomes concluded that this mutation could not rescue lethality in BRCA2-deficient mouse embryonic stem cells, supporting its classification as deleterious (Kuznetsov 2008). In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. Assessment Date: 2018/03/07.

Comment:

Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/5/2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.	Adam MP	-	2023	PMID: 20301425
Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience.	Van der Merwe NC	Frontiers in genetics	2022	DOI: 10.3389/fgene.2022.834265
Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants.	Murali K	Hereditary cancer in clinical practice	2021	PMID: 34399810
Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.	Fiala EM	Nature cancer	2021	PMID: 34308366
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.	Lerner-Ellis J	Journal of cancer research and clinical oncology	2021	PMID: 32885271
Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.	Darst BF	Journal of the National Cancer Institute	2021	PMID: 32853339
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients.	Aoude LG	Scientific reports	2020	PMID: 33077847
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes.	De Talhouet S	Scientific reports	2020	PMID: 32341426
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer.	Wu Y	European urology oncology	2020	PMID: 31948886
Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.	Zhang L	Human mutation	2020	PMID: 31444830
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: agibbs@bcm.edu	American journal of human genetics	2019	PMID: 31447099
Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer.	Petridis C	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2019	PMID: 31263054
Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance.	Abe T	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2019	PMID: 30883245
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.	Soussi T	Human mutation	2019	PMID: 30720243
Prevalence of Germline Mutations Associated With Cancer Risk in Patients With Intraductal Papillary Mucinous Neoplasms.	Skaro M	Gastroenterology	2019	PMID: 30716324
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.	Bhaskaran SP	International journal of cancer	2019	PMID: 30702160
Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes.	Wong W	Cancer	2019	PMID: 30620386
Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.	Rizzolo P	International journal of cancer	2019	PMID: 30613976
Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers.	Laitman Y	Cancer	2019	PMID: 30489631
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.	Yurgelun MB	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 29961768
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
High Prevalence of Hereditary Cancer Syndromes and Outcomes in Adults with Early-Onset Pancreatic Cancer.	Bannon SA	Cancer prevention research (Philadelphia, Pa.)	2018	PMID: 30274973
BRCA1 and BRCA2 Mutations Other Than the Founder Alleles Among Ashkenazi Jewish in the Population of Argentina.	Solano AR	Frontiers in oncology	2018	PMID: 30186769
Hereditary cancer screening: Case reports and review of literature on ten Ashkenazi Jewish founder mutations.	Cox DM	Molecular genetics & genomic medicine	2018	PMID: 30152102
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.	Sapp JC	American journal of human genetics	2018	PMID: 30122538
Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts.	Zhan W	Pancreas	2018	PMID: 30113427
Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma.	Carlo MI	JAMA oncology	2018	PMID: 29978187
Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor.	Gockley AA	Gynecologic oncology	2018	PMID: 29937315
The germline mutational landscape of BRCA1 and BRCA2 in Brazil.	Palmero EI	Scientific reports	2018	PMID: 29907814
Pathogenic Germline Variants in 10,389 Adult Cancers.	Huang KL	Cell	2018	PMID: 29625052
Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms.	Lowery MA	Journal of the National Cancer Institute	2018	PMID: 29506128
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.	Rebbeck TR	Human mutation	2018	PMID: 29446198
Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide.	Antonarakis ES	European urology	2018	PMID: 29439820
Male BRCA mutation carriers: clinical characteristics and cancer spectrum.	Ibrahim M	BMC cancer	2018	PMID: 29433453
Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer.	Isaacsson Velho P	The Prostate	2018	PMID: 29368341
BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.	Heramb C	Hereditary cancer in clinical practice	2018	PMID: 29339979
Phenotypic characteristics of colorectal cancer in BRCA1/2 mutation carriers.	Grinshpun A	European journal of human genetics : EJHG	2018	PMID: 29321669
Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.	Labidi-Galy SI	Clinical cancer research : an official journal of the American Association for Cancer Research	2018	PMID: 29084914
BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population?	Alemar B	PloS one	2017	PMID: 29161300
Mutational analysis of BRCA1 and BRCA2 genes in Peruvian families with hereditary breast and ovarian cancer.	Buleje J	Molecular genetics & genomic medicine	2017	PMID: 28944232
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.	Mandelker D	JAMA	2017	PMID: 28873162
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.	Shindo K	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28767289
Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death.	Na R	European urology	2017	PMID: 27989354
Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women.	Rebbeck TR	Breast cancer research : BCR	2016	PMID: 27836010
Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations.	Alemar B	Cancer genetics	2016	PMID: 27425403
Sanger Sequencing for BRCA1 c.68_69del, BRCA1 c.5266dup and BRCA2 c.5946del Mutation Screen on Pap Smear Cytology Samples.	Lee SH	International journal of molecular sciences	2016	PMID: 26867194
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.	Schrader KA	JAMA oncology	2016	PMID: 26556299
Patterns and functional implications of rare germline variants across 12 cancer types.	Lu C	Nature communications	2015	PMID: 26689913
Identification of germline genetic mutations in patients with pancreatic cancer.	Salo-Mullen EE	Cancer	2015	PMID: 26440929
Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup.	Miele E	Biomarker research	2015	PMID: 26064523
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions.	Lucas AL	Clinical cancer research : an official journal of the American Association for Cancer Research	2013	PMID: 23658460
Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.	George J	Clinical cancer research : an official journal of the American Association for Cancer Research	2013	PMID: 23633455
Heterozygous mutations in the PALB2 hereditary breast cancer predisposition gene impact on the three-dimensional nuclear organization of patient-derived cell lines.	Wark L	Genes, chromosomes & cancer	2013	PMID: 23341105
Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.	Novaković S	International journal of oncology	2012	PMC3583621
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.	Finkelman BS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2012	PMID: 22430266
Predictive factors for BRCA1/BRCA2 mutations in women with ductal carcinoma in situ.	Bayraktar S	Cancer	2012	PMID: 22009639
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing.	Walsh T	Proceedings of the National Academy of Sciences of the United States of America	2011	PMID: 22006311
Management of women with BRCA mutations: a 41-year-old woman with a BRCA mutation and a recent history of breast cancer.	Tung N	JAMA	2011	PMID: 21558506
Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer.	Zhang S	Gynecologic oncology	2011	PMID: 21324516
Reactive lymphoid hyperplasia in association with 22q11.2 deletion syndrome and a BRCA2 mutation.	Veerapandiyan A	European journal of medical genetics	2011	PMID: 20887823
Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control.	Janavičius R	The EPMA journal	2010	PMID: 23199084
Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.	Edwards SM	British journal of cancer	2010	PMID: 20736950
Hereditary breast and ovarian cancer due to mutations in BRCA1 and BRCA2.	Petrucelli N	Genetics in medicine : official journal of the American College of Medical Genetics	2010	PMID: 20216074
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.	Borg A	Human mutation	2010	PMID: 20104584
Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor.	Dewire MD	Pediatric blood & cancer	2009	PMID: 19530235
Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations.	Agalliu I	Clinical cancer research : an official journal of the American Association for Cancer Research	2009	PMID: 19188187
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2.	Kuznetsov SG	Nature medicine	2008	PMID: 18607349
Founder mutations in BRCA1 and BRCA2 genes.	Ferla R	Annals of oncology : official journal of the European Society for Medical Oncology	2007	PMID: 17591843
Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.	Alter BP	Journal of medical genetics	2007	PMID: 16825431
Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.	Antoniou AC	Journal of medical genetics	2005	PMID: 15994883
Functional evaluation and cancer risk assessment of BRCA2 unclassified variants.	Wu K	Cancer research	2005	PMID: 15695382
Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.	King MC	Science (New York, N.Y.)	2003	PMID: 14576434
Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia.	Offit K	Journal of the National Cancer Institute	2003	PMID: 14559878
Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations.	Satagopan JM	Clinical cancer research : an official journal of the American Association for Cancer Research	2002	PMID: 12473589
A low frequency of non-founder BRCA1 mutations in Ashkenazi Jewish breast-ovarian cancer families.	Phelan CM	Human mutation	2002	PMID: 12402332
Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals.	Frank TS	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2002	PMID: 11896095
The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.	Bahar AY	Cancer	2001	PMID: 11466700
BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer.	Moslehi R	American journal of human genetics	2000	PMID: 10739756
An unaffected individual from a breast/ovarian cancer family with germline mutations in both BRCA1 and BRCA2.	Moslehi R	Clinical genetics	2000	PMID: 10733239
Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.	Spain BH	Proceedings of the National Academy of Sciences of the United States of America	1999	PMID: 10570174
De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation.	Tesoriero A	American journal of human genetics	1999	PMID: 10417300
Double heterozygotes for the Ashkenazi founder mutations in BRCA1 and BRCA2 genes.	Friedman E	American journal of human genetics	1998	PMID: 9758598
BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and ovarian cancer.	Schubert EL	Genetic testing	1997	PMID: 10464624
Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families.	Levy-Lahad E	American journal of human genetics	1997	PMID: 9150153
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.	Struewing JP	The New England journal of medicine	1997	PMID: 9145676
The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.	Abeliovich D	American journal of human genetics	1997	PMID: 9042909
Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families.	Tonin P	Nature medicine	1996	PMID: 8898735
The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.	Oddoux C	Nature genetics	1996	PMID: 8841192
Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.	Roa BB	Nature genetics	1996	PMID: 8841191
A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals.	Berman DB	Cancer research	1996	PMID: 8758903
Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer.	Neuhausen S	Nature genetics	1996	PMID: 8673092
BRCA2 germline mutations in male breast cancer cases and breast cancer families.	Couch FJ	Nature genetics	1996	PMID: 8673091
Identification of the breast cancer susceptibility gene BRCA2.	Wooster R	Nature	1995	PMID: 8524414
Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q.	Stratton MR	Nature genetics	1994	PMID: 8075631
http://jama.jamanetwork.com/article.aspx?articleid=2214084	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8c8c6973-0686-4b0b-afb5-db5e988a2e83	-	-	-	-
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Text-mined citations for rs80359550 ...

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Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.5946del (p.Ser1982fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80359550 ...