VCV000041549.108 - ClinVar

NM_000059.4(BRCA2):c.4258G>T (p.Asp1420Tyr)

Germline

Top reviewed classifications are shown here.

Submission summary:

42 submissions

42 submitters

7 conditions

Reviewed by expert panel

Benign

Aug 2015 by Evidence-based…

for Breast-ovarian cancer, familial 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.4258G>T (p.Asp1420Tyr)

Variation ID: 41549 Accession: VCV000041549.108

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32338613 (GRCh38) [ NCBI UCSC ] 13: 32912750 (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	Dec 22, 2024	Aug 10, 2015

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.4258G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Asp1420Tyr	missense
NC_000013.11:g.32338613G>T
NC_000013.10:g.32912750G>T
NG_012772.3:g.28134G>T
LRG_293:g.28134G>T
LRG_293t1:c.4258G>T	LRG_293p1:p.Asp1420Tyr
U43746.1:n.4486G>T

... more HGVS ... less HGVS

Protein change

D1420Y

Other names

p.D1420Y:GAT>TAT
NP_000050.3:p.Asp1420Tyr
4486G>T

Canonical SPDI

NC_000013.11:32338612:G: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.

0.00399 (T)

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

1000 Genomes Project 30x 0.00359

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00396

1000 Genomes Project 0.00399

Trans-Omics for Precision Medicine (TOPMed) 0.00417

The Genome Aggregation Database (gnomAD) 0.00609

The Genome Aggregation Database (gnomAD), exomes 0.00650

Exome Aggregation Consortium (ExAC) 0.00680

Links

ClinGen: CA019810 dbSNP: rs28897727 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	19025	19184

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.
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Nov 1, 2024	RCV000034440.50
Hereditary breast ovarian cancer syndrome	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000044377.31
Breast-ovarian cancer, familial, susceptibility to, 2	Benign (14)	reviewed by expert panel	Aug 10, 2015	RCV000083103.28
not specified	Benign (10)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000120339.40
Hereditary cancer-predisposing syndrome	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Mar 26, 2020	RCV000162541.15
Breast and/or ovarian cancer	Benign (1)	criteria provided, single submitter	Jan 6, 2016	RCV000735549.11
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001353826.9

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.
Benign (Aug 10, 2015)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2015)) Method: curation	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV000244448.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 21990134 Other databases http://hci-exlovd.hci.utah.edu/v… http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.4258G%3ET Comment: IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on … (more) IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000102 (less)
Likely benign (Feb 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267017.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Likely Benign (Jan 24, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000510802.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Likely benign.
Benign (Jun 20, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805705.1 First in ClinVar: Dec 02, 2017 Last updated: Dec 02, 2017
Likely benign (Feb 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000383697.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 9971877‚ 18607349 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Dec 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069010.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (Apr 07, 2014)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary breast ovarian cancer syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000494324.2 First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022	Publications: PubMed (6) PubMed: 16905680‚ 12215251‚ 18284688‚ 15635067‚ 14507240‚ 23767878
Benign (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002550334.4 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Oct 23, 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: SCV000602780.8 First in ClinVar: Sep 28, 2017 Last updated: Feb 20, 2024
Benign (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: SCV000195982.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Tissue: Blood
Benign (Mar 05, 2015)	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: SCV000292117.1 First in ClinVar: Jul 08, 2016 Last updated: Jul 08, 2016
Likely benign (Aug 26, 2015)	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: SCV000575731.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015
Benign (Apr 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000586948.1 First in ClinVar: Oct 22, 2016 Last updated: Oct 22, 2016
Benign (Oct 09, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167364.11 First in ClinVar: Jun 23, 2014 Last updated: Dec 02, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Oct 09, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743297.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (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: SCV000744454.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Nov 12, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000225172.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 02, 2017	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2 http://exac.broadinstitute.org/v… http://exac.broadinstitute.org/variant/13-32912750-G-T http://www.umd.be/BRCA2/ http://www.umd.be/BRCA2/ Number of individuals with the variant: 3 Zygosity: Single Heterozygote Sex: mixed
Benign (Jan 06, 2016)	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: SCV000219337.4 First in ClinVar: Mar 29, 2015 Last updated: May 06, 2019
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001139086.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Benign (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: SCV002026101.1 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)
Benign (Nov 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary breast ovarian cancer syndrome Affected status: yes Allele origin: germline	Genetics Program, Instituto Nacional de Cancer Accession: SCV002515273.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (1) PubMed: 36329109 Geographic origin: Brazil
Benign (Mar 26, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002533860.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Jan 02, 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: SCV000154044.2 First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 21702907‚ 21952622‚ 22703879‚ 9971877‚ 21520273
Benign (Aug 24, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	Hereditary Breast and Ovarian Cancer Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000296855.3 First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022
Benign (Feb 01, 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: SCV000072390.14 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024
Benign (Nov 19, 2014)	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: SCV000212944.6 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Likely benign (Nov 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: SCV000692771.31 First in ClinVar: Mar 08, 2017 Last updated: Dec 22, 2024	Comment: BRCA2: BP4, BS2 Number of individuals with the variant: 58
Benign (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004016851.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005236053.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Dec 12, 2016)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778674.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Likely benign (-)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863687.2 First in ClinVar: Dec 24, 2018 Last updated: Apr 23, 2022
no known pathogenicity (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043208.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Benign. Number of individuals with the variant: 6 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)
Likely benign (Jul 24, 2014)	no assertion criteria provided Method: literature only	hereditary breast and ovarian cancer, BROVCA2 Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000187734.1 First in ClinVar: Aug 15, 2014 Last updated: Aug 15, 2014	Publications: PubMed (3) PubMed: 22703879‚ 24728327‚ 12215251
Benign (May 01, 2012)	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: SCV000115177.3 First in ClinVar: Feb 06, 2014 Last updated: Sep 27, 2014
Benign (-)	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: SCV000733255.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jan 05, 2018)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000787930.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018
Benign (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast 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: SCV000591897.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and … (more) The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and was also identified in 109 of 8530 (frequency of 0.013) control chromosomes increasing the likelihood that this is a low frequency benign variant It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897727) with a global minor allele frequency (MAF) of 0.001/2, and has an average heterozygosity of 0.008+/-0.062, increasing the likelihood that it is a benign variant. The Asp1420 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Functional studies have shown that compared to the wild-type protein, the p.Asp1420Tyr variant showed similar repair capacity and protein interactions, particularly with RAD51 (Davies_2001_11239456, Galkin_2005_15937124, Kuznetsov_2008_18607349). In addition, in two studies, one of which was a case control study, the allele frequency was higher in controls compared to the proband (Dombernowsky_2009_19661094, Stuppia_2003_12872265), thereby increasing the likelihood that this variant does not have clinical significance. Myriad genetics classifies this variant as a polymorphism, increasing the likelihood this variant is benign. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in these individuals, but based on the above information this variant is classified as benign. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797615.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001906316.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001958459.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000146395.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 92 Observation 2: Number of individuals with the variant: 1 Geographic origin: African American Observation 3: Number of individuals with the variant: 8 Geographic origin: Austria Observation 4: Number of individuals with the variant: 1 Geographic origin: Central/Eastern European Observation 5: Number of individuals with the variant: 1 Geographic origin: French Canadian Observation 6: Number of individuals with the variant: 2 Geographic origin: Germany Observation 7: Number of individuals with the variant: 1 Geographic origin: Ireland Observation 8: Number of individuals with the variant: 1 Geographic origin: Scottish Observation 9: Number of individuals with the variant: 20 Geographic origin: Western European Observation 10: Number of individuals with the variant: 1 Geographic origin: Western European, Latin American, Caribbean Observation 11: Number of individuals with the variant: 1 Geographic origin: Western, Central/Eastern European Observation 12: Number of individuals with the variant: 1 Ethnicity/Population group: Arab Geographic origin: Saudi Arabia Observation 13: Number of individuals with the variant: 2 Ethnicity/Population group: Ashkenazi Observation 14: Number of individuals with the variant: 1 Ethnicity/Population group: Ashkenazi, Western European Observation 15: Number of individuals with the variant: 1 Ethnicity/Population group: Austrian Observation 16: Number of individuals with the variant: 2 Ethnicity/Population group: Caucasian Observation 17: Number of individuals with the variant: 2 Ethnicity/Population group: Caucasian Geographic origin: Germany Observation 18: Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Spain Observation 19: Number of individuals with the variant: 4 Ethnicity/Population group: Central/Eastern European Observation 20: Number of individuals with the variant: 1 Ethnicity/Population group: German Geographic origin: American Observation 21: Number of individuals with the variant: 1 Ethnicity/Population group: Irish German Dutch Observation 22: Number of individuals with the variant: 1 Ethnicity/Population group: Latin American, Caribbean Observation 23: Number of individuals with the variant: 2 Ethnicity/Population group: Native American Observation 24: Number of individuals with the variant: 1 Ethnicity/Population group: Native American, Western European Observation 25: Number of individuals with the variant: 51 Ethnicity/Population group: Western European Observation 26: Number of individuals with the variant: 1 Ethnicity/Population group: Western, Central/Eastern European
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084491.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The p.Asp1420Tyr variant has been previously reported in the literature in 203 of 18968 proband chromosomes (frequency of 0.011) with breast and ovarian cancer, and was also identified in 109 of 8530 (frequency of 0.013) control chromosomes increasing the likelihood that this is a low frequency benign variant It is listed in dbSNP database as coming from a "clinical source" (ID#: rs28897727) with a global minor allele frequency (MAF) of 0.001/2, and has an average heterozygosity of 0.008+/-0.062, increasing the likelihood that it is a benign variant. The Asp1420 residue is not highly conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Functional studies have shown that compared to the wild-type protein, the p.Asp1420Tyr variant showed similar repair capacity and protein interactions, particularly with RAD51 (Davies_2001_11239456, Galkin_2005_15937124, Kuznetsov_2008_18607349). In addition, in two studies, one of which was a case control study, the allele frequency was higher in controls compared to the proband (Dombernowsky_2009_19661094, Stuppia_2003_12872265), thereby increasing the likelihood that this variant does not have clinical significance. Myriad genetics classifies this variant as a polymorphism, increasing the likelihood this variant is benign. In summary, we cannot rule out the possibility that this variant may contribute to the phenotype in these individuals, but based on the above information this variant is classified as benign.

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
Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service.	Matta BP	Scientific reports	2022	PMID: 36329109
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
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
BRCA1/2 mutation screening in high-risk breast/ovarian cancer families and sporadic cancer patient surveilling for hidden high-risk families.	Berzina D	BMC medical genetics	2013	PMID: 23767878
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
A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).	Lindor NM	Human mutation	2012	PMID: 21990134
BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.	Kote-Jarai Z	British journal of cancer	2011	PMID: 21952622
A high-throughput protocol for mutation scanning of the BRCA1 and BRCA2 genes.	Hondow HL	BMC cancer	2011	PMID: 21702907
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.	Capanu M	Genetic epidemiology	2011	PMID: 21520273
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2.	Kuznetsov SG	Nature medicine	2008	PMID: 18607349
Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.	Lee E	Breast cancer research : BCR	2008	PMID: 18284688
Evaluation of BRCA1 and BRCA2 mutation prevalence, risk prediction models and a multistep testing approach in French-Canadian families with high risk of breast and ovarian cancer.	Simard J	Journal of medical genetics	2007	PMID: 16905680
Prevalence of BRCA2 mutations in a hospital based series of unselected breast cancer cases.	Kim SW	Journal of medical genetics	2005	PMID: 15635067
BRCA1, BRCA2 and CHEK2 (1100 del C) germline mutations in hereditary breast and ovarian cancer families in South India.	Rajkumar T	Asian Pacific journal of cancer prevention : APJCP	2003	PMID: 14507240
Characterization of common BRCA1 and BRCA2 variants.	Deffenbaugh AM	Genetic testing	2002	PMID: 12215251
Global sequence diversity of BRCA2: analysis of 71 breast cancer families and 95 control individuals of worldwide populations.	Wagner TM	Human molecular genetics	1999	PMID: 9971877
http://exac.broadinstitute.org/variant/13-32912750-G-T	-	-	-	-
http://hci-exlovd.hci.utah.edu/variants.php?select_db=BRCA2&action=search_all&search_Variant%2FDNA=c.4258G%3ET	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
http://www.umd.be/BRCA2/	-	-	-	-
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Text-mined citations for rs28897727 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.4258G>T (p.Asp1420Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28897727 ...