Submissions for variant NM_000059.4(BRCA2):c.2837A>G (p.Asp946Gly)

gnomAD frequency: 0.00001  dbSNP: rs55972907

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132081	SCV000187145	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	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.
GeneDx	RCV000588917	SCV000210294	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	Observed in a woman with breast cancer diagnosed under age 35 who also carried a second BRCA2 missense variant (Encinas et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3065A>G; This variant is associated with the following publications: (PMID: 23929434, 20858050, 29884841, 32377563, 29854292)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855581	SCV000694637	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2837A>G (p.Asp946Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250610 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2837A>G has been reported in the literature in at least one individual affected with breast cancer (Encinas_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) in the NHGRI BIC database have been reported (BRCA2 c.5454delA, p.Cys1820AlafsX20), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2023). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 37922907, 20858050, 29854292, 23929434). ClinVar contains an entry for this variant (Variation ID: 51358). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000113103	SCV000786586	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-06-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132081	SCV000906894	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 946 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 29854292). This variant has also been identified in 1/250610 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001445276	SCV001648303	likely benign	Hereditary breast ovarian cancer syndrome	2024-10-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132081	SCV003850174	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113103	SCV000146128	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing