Submissions for variant NM_000059.4(BRCA2):c.6125A>G (p.Gln2042Arg)

gnomAD frequency: 0.00002  dbSNP: rs80358852

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160108	SCV000210383	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 6353A>G; Observed in individuals with a personal and/or family history of breast, ovarian, or prostate cancer (Li et al., 2020); This variant is associated with the following publications: (PMID: 31131967, 31911673, 32377563, 29884841, 31853058)
Invitae	RCV000200820	SCV000254199	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000219164	SCV000276482	likely benign	Hereditary cancer-predisposing syndrome	2020-03-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000031600	SCV000784909	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000219164	SCV000911401	likely benign	Hereditary cancer-predisposing syndrome	2017-06-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779953	SCV000916909	uncertain significance	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6125A>G (p.Gln2042Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 143300 control chromosomes, predominantly at a frequency of 0.00036 within the African or African-American subpopulation in the gnomAD v3 database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.0001 vs 0.00075), allowing no conclusion about variant significance. c.6125A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome, however without strong evidence for causality (e.g., Gorringe_2008, Brahim_2022). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, although functionally validated computational prediction models suggest the variant has a neutral impact on protein function (e.g., Hart_2019). The following publications have been ascertained in the context of this evaluation (PMID: 35858847, 17972171, 31853058, 29884841). The variant has been reported in the FLOSSIES database in 3 women older than age 70 years who have never had cancer, providing supporting evidence for a benign role. Seven ClinVar submitters (evaluation after 2014) have cited the variant as either uncertain significance (n = 3) or likely benign (n = 4). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000779953	SCV002046593	uncertain significance	not specified	2021-05-26	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000219164	SCV003850958	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).
Sharing Clinical Reports Project (SCRP)	RCV000031600	SCV000054207	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-02-20	no assertion criteria provided	clinical testing