Submissions for variant NM_000059.4(BRCA2):c.7786G>A (p.Gly2596Arg)

dbSNP: rs398122591

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160142	SCV000210447	uncertain significance	not provided	2020-03-04	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8014G>A; Published functional studies demonstrate impaired homology directed repair activity (Guidugli 2018, Hart 2018); This variant is associated with the following publications: (PMID: 29394989, 30254663, 29884841)
Invitae	RCV000197789	SCV000254212	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2596 of the BRCA2 protein (p.Gly2596Arg). This variant is present in population databases (rs398122591, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 30613976). ClinVar contains an entry for this variant (Variation ID: 91492). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29884841, 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160142	SCV000296520	uncertain significance	not provided	2020-01-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000077009	SCV000489011	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509715	SCV000608032	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The p.G2596R variant (also known as c.7786G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7786. The glycine at codon 2596 is replaced by arginine, an amino acid with dissimilar properties. Three separate homology-directed DNA repair (HDR) assays have demonstrated p.G2596R is non-functional (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Hart SN et al. Genet. Med., 2019 01;21:71-80; Richardson ME et al. Am J Hum Genet, 2021 Mar;108:458-468). Another alteration at the same codon, p.G2596E (c.7787G>A), has been described as having low functionality in a HDR assay (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000509715	SCV000683904	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770731	SCV000902212	uncertain significance	Breast and/or ovarian cancer	2017-05-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000197789	SCV001623182	likely pathogenic	Hereditary breast ovarian cancer syndrome	2021-04-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7786G>A (p.Gly2596Arg) results in a non-conservative amino acid change located in the breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251378 control chromosomes. c.7786G>A has been reported in the literature as a VUS in at-least one individual affected with male breast cancer (Rizzolo_2019). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of normal homology directed repair (HDR) activity and a non-functional impact using a well-established mouse embryonic stem cell based assay (example, Biswas_2020, Guidugli_2018). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6). At-least one submitter reports a likely pathogenic classiciation using overlapping functional evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003460727	SCV004216004	uncertain significance	Familial cancer of breast	2023-07-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077009	SCV000108806	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-03-23	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077009	SCV004228443	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PS3(Strong)+PM2(Supporting)+PP3(Supporting)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)