Submissions for variant NM_000059.4(BRCA2):c.2779A>G (p.Met927Val)

dbSNP: rs786201837

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164328	SCV000214959	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	clinical testing	The p.M927V variant (also known as c.2779A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2779. The methionine at codon 927 is replaced by valine, an amino acid with highly similar properties. Two functional studies have used homologous recombination (HR) based assays to show that this alteration increases the rate of HR comparable to wild-type BRCA2 and is therefore likely non-pathogenic (Balia C et al. Breast Cancer Res Treat. 2011 Oct;129(3):1001-9; Spugnesi L et al. Mutagenesis. 2013 Mar;28(2):187-95). Balia et al also noted that the tumor from the individual with this alteration did not show loss of heterozygosity, and while the data was not shown, the authors mentioned that this variant did not segregate with disease in the family. This alteration has also been reported in two individuals from the same Serbian family, both with breast cancer (Dobricic J et al. J Hum Genet. 2013 Aug;58(8):501-7). Of note, this alteration is also designated as 3007A>G in published literature. 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.
GeneDx	RCV000426572	SCV000521705	likely benign	not specified	2017-11-16	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000525226	SCV000635245	likely benign	Hereditary breast ovarian cancer syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000426572	SCV000694625	uncertain significance	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2779A>G (p.Met927Val) 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 was absent in 250872 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2779A>G has been reported in the literature as not co-segregating with disease in at-least one family affected with Hereditary Breast and Ovarian Cancer (HBOC) (example, Balia_2011) and in at-least two individuals from high risk families using an in-silico tool (Polyphen) as the basis of causality (Dobricic_2013). These report(s) 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 (Balia_2011). These results showed no damaging effect of this variant on BRCA2 DNA repair activity in a yeast based experimental system. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, pending independent corroboration of the reported neutral functional outcome by another independent study, the variant was classified as VUS-possibly benign.
Counsyl	RCV000663056	SCV000786108	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164328	SCV000906050	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 927 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). Functional studies using a homology-mediated DNA repair assay that examines low-frequency spontaneous repair events and a yeast DNA repair assay have both shown this variant protein to be repair proficient (PMID: 21671020, 23328489). This variant has been reported in families and individuals affected with breast/ovarian cancer (PMID: 21671020, 23635950, 35402282). This variant has been reported in a multifactorial analysis as likely benign based in part to segregation and family history likelihood ratios (PMID: 31131967). This variant has not been identified 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262846	SCV001440869	likely benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588268	SCV001469672	uncertain significance	not provided	2020-09-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV001262846	SCV002580252	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BP5_SUP, PM2_SUP
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164328	SCV003850128	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).
Myriad Genetics, Inc.	RCV000663056	SCV004018657	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].