VCV000052134.29 - ClinVar

NM_000059.4(BRCA2):c.6613G>A (p.Val2205Met)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(14)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(7); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000059.4(BRCA2):c.6613G>A (p.Val2205Met)

Variation ID: 52134 Accession: VCV000052134.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q13.1 13: 32340968 (GRCh38) [ NCBI UCSC ] 13: 32915105 (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	May 1, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000059.4:c.6613G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000050.3:p.Val2205Met	missense
NC_000013.11:g.32340968G>A
NC_000013.10:g.32915105G>A
NG_012772.3:g.30489G>A
LRG_293:g.30489G>A
LRG_293t1:c.6613G>A	LRG_293p1:p.Val2205Met
U43746.1:n.6841G>A

... more HGVS ... less HGVS

Protein change

V2205M

Other names

p.V2205M:GTG>ATG
6841G>A

Canonical SPDI

NC_000013.11:32340967:G:A

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.

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA024211 dbSNP: rs80358889 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	18967	19126

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.
Breast-ovarian cancer, familial, susceptibility to, 2	Uncertain significance (5)	criteria provided, multiple submitters, no conflicts	Oct 9, 2019	RCV000077379.15
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 5, 2023	RCV000166043.25
Hereditary breast ovarian cancer syndrome	Likely benign (1)	criteria provided, single submitter	Dec 13, 2023	RCV000195375.20
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	May 11, 2023	RCV000588118.17
Breast and/or ovarian cancer	Uncertain significance (1)	criteria provided, single submitter	Mar 31, 2017	RCV000769700.10

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.
Uncertain significance (Aug 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821945.1 First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018
Uncertain significance (Mar 31, 2017)	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: SCV000901117.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Uncertain significance (Oct 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001481781.2 First in ClinVar: Feb 27, 2021 Last updated: Feb 27, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Likely benign (Feb 14, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000210396.12 First in ClinVar: Feb 24, 2015 Last updated: Mar 13, 2019	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25136594, 20104584, 26306726, … (more) In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25136594, 20104584, 26306726, 24504028, 29335924, 29310832, 31159747, 31131967) (less)
Likely benign (Mar 11, 2021)	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: SCV000902984.3 First in ClinVar: May 20, 2019 Last updated: Jan 08, 2022
Uncertain significance (Feb 18, 2016)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488305.2 First in ClinVar: Sep 27, 2014 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 26306726‚ 24504028‚ 25136594‚ 20104584‚ 24817641
Likely benign (Mar 23, 2023)	criteria provided, single submitter (Dines et al. (Genet Med. 2020)) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV003847313.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 Comment: BRCA2 exon 11 coldspot. Reclassification based on statistical prior probability.	Publications: PubMed (1) PubMed: 31911673 Comment: Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Uncertain significance (May 11, 2023)	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: SCV000889106.4 First in ClinVar: Mar 13, 2019 Last updated: Jan 06, 2024	Publications: PubMed (11) PubMed: 20104584‚ 25136594‚ 31911673‚ 31159747‚ 26306726‚ 29310832‚ 24504028‚ 29335924‚ 31131967‚ 24817641‚ 21520273 Comment: The frequency of this variant in the general population, 0.000054 (6/111976 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.000054 (6/111976 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 20104584 (2010), 21520273 (2011), 29335924 (2018)), ovarian cancer (PMID: 24504028 (2014), 26306726 (2015)), and familial breast and/or ovarian cancer (PMID: 25136594 (2014), 29310832 (2018), 31159747 (2019)). Additionally, a multifactorial likelihood analysis predicts that the variant is likely benign (PMID: 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Likely benign (Dec 13, 2023)	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: SCV000073006.13 First in ClinVar: Jul 03, 2013 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (Mar 03, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000694983.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (6) PubMed: 24817641‚ 24504028‚ 26306726‚ 20104584‚ 25136594‚ 21520273 Comment: Variant summary: The BRCA2 c.6613G>A (p.Val2205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a … (more) Variant summary: The BRCA2 c.6613G>A (p.Val2205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120326 (1/24038), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals (BrC, OvC, HBOC), however, with limited information (ie lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)." (less)
Uncertain significance (Jul 05, 2023)	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: SCV000216804.8 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 20104584‚ 21520273‚ 24504028‚ 25136594‚ 26306726‚ 29310832 Comment: The p.V2205M variant (also known as c.6613G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide … (more) The p.V2205M variant (also known as c.6613G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6613. The valine at codon 2205 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal history of breast and/or ovarian cancer (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Capanu M et al. Genet. Epidemiol., 2011 Jul;35:389-97; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Ruiz A et al. Biomed Res Int. 2014 Jun;2014:54254; Minucci A et al. Expert Rev. Mol. Diagn. 2015 Aug;15:1383-4031) and in a cohort of individuals referred for genetic analysis of the BRCA1 and BRCA2 genes (Apessos A et al. Cancer Genet, 2018 Jan;220:1-12). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (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: SCV000146891.1 First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014	Number of individuals with the variant: 1 Ethnicity/Population group: Western European, Italian
Uncertain significance (Mar 02, 2020)	no assertion criteria provided Method: clinical testing	Breast-ovarian cancer, familial, susceptibility to, 2 Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV004243729.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024
Uncertain significance (May 15, 2008)	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: SCV000109176.2 First in ClinVar: Dec 23, 2013 Last updated: Sep 27, 2014
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Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25136594, 20104584, 26306726, 24504028, 29335924, 29310832, 31159747, 31131967)

Comment:

The frequency of this variant in the general population, 0.000054 (6/111976 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 20104584 (2010), 21520273 (2011), 29335924 (2018)), ovarian cancer (PMID: 24504028 (2014), 26306726 (2015)), and familial breast and/or ovarian cancer (PMID: 25136594 (2014), 29310832 (2018), 31159747 (2019)). Additionally, a multifactorial likelihood analysis predicts that the variant is likely benign (PMID: 31131967 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

Variant summary: The BRCA2 c.6613G>A (p.Val2205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120326 (1/24038), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals (BrC, OvC, HBOC), however, with limited information (ie lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

Comment:

The p.V2205M variant (also known as c.6613G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6613. The valine at codon 2205 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with a personal history of breast and/or ovarian cancer (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Capanu M et al. Genet. Epidemiol., 2011 Jul;35:389-97; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Ruiz A et al. Biomed Res Int. 2014 Jun;2014:54254; Minucci A et al. Expert Rev. Mol. Diagn. 2015 Aug;15:1383-4031) and in a cohort of individuals referred for genetic analysis of the BRCA1 and BRCA2 genes (Apessos A et al. Cancer Genet, 2018 Jan;220:1-12). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".	Dines JN	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 31911673
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
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
BRCA1 and BRCA2 germline variants in breast cancer patients from the Republic of Macedonia.	Jakimovska M	Breast cancer research and treatment	2018	PMID: 29335924
Comprehensive BRCA mutation analysis in the Greek population. Experience from a single clinical diagnostic center.	Apessos A	Cancer genetics	2018	PMID: 29310832
Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review.	Minucci A	Expert review of molecular diagnostics	2015	PMID: 26306726
Genetic testing in hereditary breast and ovarian cancer using massive parallel sequencing.	Ruiz A	BioMed research international	2014	PMID: 25136594
An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex.	Doss CG	Cell biochemistry and biophysics	2014	PMID: 24817641
Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status.	Cunningham JM	Scientific reports	2014	PMID: 24504028
Assessment of rare BRCA1 and BRCA2 variants of unknown significance using hierarchical modeling.	Capanu M	Genetic epidemiology	2011	PMID: 21520273
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
The breast cancer information core: database design, structure, and scope.	Szabo C	Human mutation	2000	PMID: 10923033
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Text-mined citations for rs80358889 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000059.4(BRCA2):c.6613G>A (p.Val2205Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80358889 ...