Submissions for variant NM_000059.4(BRCA2):c.6231G>C (p.Lys2077Asn)

gnomAD frequency: 0.00001  dbSNP: rs541826447

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087043	SCV000166180	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222718	SCV000277170	likely benign	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Counsyl	RCV000412472	SCV000488080	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222718	SCV000683762	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 2077 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 5 individuals affected with breast and/or ovarian cancer, 1 individual affected with prostate cancer, and in 2 unaffected individuals (PMID: 28993434, 29470806, 29785135, 33471991; Leiden Open Variation Database DB-ID BRCA2_003775, 36259290 , 37277882). This variant has been identified in 29/248688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267862	SCV000694949	likely benign	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6231G>C (p.Lys2077Asn) results in a non-conservative amino acid change located in the BRCA2 repeat (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249782 control chromosomes (gnomAD, Wen_2018), predominantly at a frequency of 0.00096 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.6231G>C has been reported in the literature in individuals affected with Breast/Ovarian Cancer (e.g. Kurian_2008, Singh_2018, Sirisena_2020, Dorling_2021) and Prostate cancer (Satapathy_2023) without evidence for causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant was able to rescue Brca2-deficient mouse embryonic stem cells exposed to DNA damaging agents (Sirisena_2020). The following publications have been ascertained in the context of this evaluation (PMID: 18779604, 36259290, 29470806, 32393398, 28993434, 33471991). Nine ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002267862	SCV001133857	likely benign	not specified	2023-10-16	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001087043	SCV002025796	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000588715	SCV002547271	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Kurian et al., 2008; Mannan et al., 2016; Shah et al., 2018; Singh et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: comparable to wild-type in ability to rescue cell lethality and lack of response to DNA-damaging agents, as measured in mouse embryonic stem cell-based functional assay (Sirisena et al., 2020); Also known as 6459G>C; This variant is associated with the following publications: (PMID: 18779604, 35464868, 26911350, 32393398, 28726806, 9002670, 22193408, 29470806, 28993434, 29785135)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267862	SCV002551379	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000222718	SCV003852337	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000412472	SCV004846720	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 2077 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 5 individuals affected with breast and/or ovarian cancer, 1 individual affected with prostate cancer, and in 2 unaffected individuals (PMID: 28993434, 29470806, 29785135, 33471991; Leiden Open Variation Database DB-ID BRCA2_003775, 36259290 , 37277882). This variant has been identified in 29/248688 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.