VCV000052606.93 - ClinVar

NM_000059.4(BRCA2):c.8503T>C (p.Ser2835Pro)

Germline

Top reviewed classifications are shown here.

Submission summary:

32 submissions

31 submitters

9 conditions

Reviewed by expert panel

Benign

Jun 2019 by Evidence-based…

for Breast-ovarian cancer, familial, susceptibility to, 2

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.8503T>C (p.Ser2835Pro)

Variation ID: 52606 Accession: VCV000052606.93

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32370971 (GRCh38) [ NCBI UCSC ] 13: 32945108 (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 1, 2014	Dec 22, 2024	Jun 18, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.8503T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Ser2835Pro	missense
NC_000013.11:g.32370971T>C
NC_000013.10:g.32945108T>C
NG_012772.3:g.60492T>C
LRG_293:g.60492T>C
LRG_293t1:c.8503T>C	LRG_293p1:p.Ser2835Pro
U43746.1:n.8731T>C

... more HGVS ... less HGVS

Protein change

S2835P

Other names

p.S2835P:TCA>CCA

Canonical SPDI

NC_000013.11:32370970:T:C

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.

0.00140 (C)

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

The Genome Aggregation Database (gnomAD), exomes 0.00055

Exome Aggregation Consortium (ExAC) 0.00073

1000 Genomes Project 0.00140

1000 Genomes Project 30x 0.00141

The Genome Aggregation Database (gnomAD) 0.00202

Trans-Omics for Precision Medicine (TOPMed) 0.00220

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00231

Links

ClinGen: CA025684 dbSNP: rs11571746 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	19029	19191

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 specified	Benign/Likely benign (9)	criteria provided, multiple submitters, no conflicts	Aug 15, 2023	RCV000120364.36
Hereditary cancer-predisposing syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Oct 8, 2020	RCV000129146.16
Breast-ovarian cancer, familial, susceptibility to, 2	Benign (8)	reviewed by expert panel	Jun 18, 2019	RCV000113950.27
Hereditary breast ovarian cancer syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000167840.28
not provided	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000656624.44
Breast and/or ovarian cancer	Benign (2)	criteria provided, single submitter	Aug 29, 2022	RCV000735612.10
Fanconi anemia complementation group D1	Likely benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV001110062.12
Breast-ovarian cancer, familial, susceptibility to, 2 Familial cancer of breast Fanconi anemia complementation group D1 Glioma susceptibility 3 Malignant tumor of prostate Medulloblastoma Pancreatic cancer, susceptibility to, 2 Wilms tumor 1	Likely benign (1)	criteria provided, single submitter	Feb 7, 2022	RCV002483047.8
BRCA2-related cancer predisposition	Likely benign (1)	criteria provided, single submitter	Sep 24, 2024	RCV004803917.1

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 (Jun 18, 2019)	reviewed by expert panel (ENIGMA BRCA1/2 Classification Criteria (2017-06-29)) Method: curation	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: germline	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Accession: SCV001161621.2 First in ClinVar: Feb 16, 2020 Last updated: Jan 07, 2023	Publications: PubMed (1) PubMed: 31131967 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 = 0.000863 (less)
Benign (Jan 28, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000167411.11 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)
Likely benign (Mar 06, 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: SCV000383785.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely benign (Jan 04, 2022)	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: SCV002068922.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Mar 20, 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: SCV000154089.2 First in ClinVar: Jun 09, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 17341484‚ 22425665‚ 18284688‚ 19043619‚ 10717622
Likely benign (Feb 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Medulloblastoma Familial prostate cancer Wilms tumor 1 Fanconi anemia complementation group D1 Breast-ovarian cancer, familial, susceptibility to, 2 Glioma susceptibility 3 Pancreatic cancer, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002798772.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 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: SCV000073553.15 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024
Likely Benign (Sep 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	BRCA2-related cancer predisposition (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004846027.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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)	Number of individuals with the variant: 145 Zygosity: Single Heterozygote
Benign (Oct 30, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000223756.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 2015	Publications: PubMed (2) PubMed: 24728327‚ 22425665 Other databases http://www.1000genomes.org http://www.1000genomes.org
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000538476.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (77/10388) African chromosomes (less) Method: Genome/Exome Filtration
Benign (Dec 16, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227606.5 First in ClinVar: Jun 28, 2015 Last updated: Sep 22, 2018	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: 3 Zygosity: Single Heterozygote Sex: mixed
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: SCV001139219.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Likely benign (Mar 06, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group D1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001267451.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Likely 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: SCV002515155.1 First in ClinVar: Nov 19, 2022 Last updated: Nov 19, 2022	Publications: PubMed (1) PubMed: 36329109 Geographic origin: Brazil
Benign (Oct 08, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002531953.1 First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020
Benign (Sep 29, 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: SCV000494354.2 First in ClinVar: Feb 04, 2017 Last updated: Dec 11, 2022	Publications: PubMed (11) PubMed: 17341484‚ 23683081‚ 19043619‚ 18284688‚ 19799798‚ 22684231‚ 24123850‚ 12491487‚ 16284991‚ 22425665‚ 22505045
Likely benign (Apr 24, 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: SCV000683973.2 First in ClinVar: Feb 19, 2018 Last updated: Dec 11, 2022
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: SCV004016859.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023
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: SCV002551826.3 First in ClinVar: Jul 30, 2022 Last updated: Aug 18, 2023
Benign (Aug 29, 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 Accession: SCV004240366.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Likely benign (Mar 31, 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: SCV000885095.6 First in ClinVar: Jun 25, 2018 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: SCV000183867.7 First in ClinVar: Aug 06, 2014 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)
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: SCV005236539.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (May 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: SCV001371333.25 First in ClinVar: Jul 16, 2020 Last updated: Dec 22, 2024	Comment: BRCA2: BP4 Number of individuals with the variant: 5
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: SCV001952953.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (May 29, 2002)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial 2 Affected status: yes Allele origin: germline	Breast Cancer Information Core (BIC) (BRCA2) Accession: SCV000147386.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Observation 1: Number of individuals with the variant: 11 Observation 2: Number of individuals with the variant: 1 Geographic origin: African American Observation 3: Number of individuals with the variant: 1 Geographic origin: Western European Observation 4: Number of individuals with the variant: 10 Ethnicity/Population group: African Observation 5: Number of individuals with the variant: 1 Ethnicity/Population group: African, Central/Eastern European Observation 6: Number of individuals with the variant: 1 Ethnicity/Population group: Asian Observation 7: Number of individuals with the variant: 2 Ethnicity/Population group: Latin American, Caribbean Observation 8: Number of individuals with the variant: 1 Ethnicity/Population group: Native American, African American Observation 9: Number of individuals with the variant: 5 Ethnicity/Population group: Western European Observation 10: Number of individuals with the variant: 1 Ethnicity/Population group: Western European, African, Latin American, Caribbean
Likely benign (Feb 05, 2018)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000778719.1 First in ClinVar: Jun 25, 2018 Last updated: Jun 25, 2018
Benign (Apr 13, 2013)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000863750.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018
Benign (-)	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: SCV000592204.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Ser2835Pro variant has been identified in 7 out of 7570 proband chromosomes (frequency 0.001) in individuals with cutaneous malignant melanoma, and breast and ovarian … (more) The p.Ser2835Pro variant has been identified in 7 out of 7570 proband chromosomes (frequency 0.001) in individuals with cutaneous malignant melanoma, and breast and ovarian cancer phenotypes, and identified in 1 out of 5064 control chromosomes (frequency <0.001) (Casula 2006, Caux-Moncoutier 2011, Frackenthal 2012, Johnson 2007, Palomba 2009, Tazzite 2012, Malone 2000, Karchin 2008, Schoumacher 2001). It is listed in dbSNP database as coming from a â€šÃ„Ãºclinical sourceâ€šÃ„Ã¹ (ID#: rs11571746) however no frequency information was provided. The variant is identified in the EVS server as a low frequency variant increasing the likelihood this variant does not have clinical significance. The p.Ser2835 is not conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and the variant amino acid Proline (Pro) residue is present in cat, dog and zebrafish, suggesting this variant may not be functionally important. In the UMD database, this variant has been identified in 2 (out of 13) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. In addition, it is presented 34 times in the BIC database as a variant with no clinical significance. In summary based on the information presented above this variant is classified as benign. (less) Number of individuals with the variant: 2
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: SCV001905689.1 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001967551.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000084516.1 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 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 variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (77/10388) African chromosomes

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.Ser2835Pro variant has been identified in 7 out of 7570 proband chromosomes (frequency 0.001) in individuals with cutaneous malignant melanoma, and breast and ovarian cancer phenotypes, and identified in 1 out of 5064 control chromosomes (frequency <0.001) (Casula 2006, Caux-Moncoutier 2011, Frackenthal 2012, Johnson 2007, Palomba 2009, Tazzite 2012, Malone 2000, Karchin 2008, Schoumacher 2001). It is listed in dbSNP database as coming from a â€šÃ„Ãºclinical sourceâ€šÃ„Ã¹ (ID#: rs11571746) however no frequency information was provided. The variant is identified in the EVS server as a low frequency variant increasing the likelihood this variant does not have clinical significance. The p.Ser2835 is not conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and the variant amino acid Proline (Pro) residue is present in cat, dog and zebrafish, suggesting this variant may not be functionally important. In the UMD database, this variant has been identified in 2 (out of 13) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. In addition, it is presented 34 times in the BIC database as a variant with no clinical significance. In summary based on the information presented above 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
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.	Parsons MT	Human mutation	2019	PMID: 31131967
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Capillary electrophoresis analysis of conventional splicing assays: IARC analytical and clinical classification of 31 BRCA2 genetic variants.	de Garibay GR	Human mutation	2014	PMID: 24123850
Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain).	Blay P	BMC cancer	2013	PMID: 23683081
BRCA1 and BRCA2 unclassified variants and missense polymorphisms in Algerian breast/ovarian cancer families.	Cherbal F	Disease markers	2012	PMID: 22684231
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.	Houdayer C	Human mutation	2012	PMID: 22505045
BRCA1 and BRCA2 germline mutations in Moroccan breast/ovarian cancer families: novel mutations and unclassified variants.	Tazzite A	Gynecologic oncology	2012	PMID: 22425665
Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy.	Casula M	BMC cancer	2009	PMID: 19799798
Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.	Karchin R	Cancer informatics	2008	PMID: 19043619
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
Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility.	Johnson N	Human molecular genetics	2007	PMID: 17341484
BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.	Pal T	Cancer	2005	PMID: 16284991
Breast cancer genetics in African Americans.	Olopade OI	Cancer	2003	PMID: 12491487
The breast cancer information core: database design, structure, and scope.	Szabo C	Human mutation	2000	PMID: 10923033
Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases.	Malone KE	Cancer	2000	PMID: 10717622
http://www.1000genomes.org	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=BRCA2	-	-	-	-
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Text-mined citations for rs11571746 ...

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.8503T>C (p.Ser2835Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11571746 ...