Submissions for variant NM_000059.4(BRCA2):c.7787G>A (p.Gly2596Glu)

dbSNP: rs1064795140

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485136	SCV000570647	likely pathogenic	not provided	2024-11-18	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired homology-directed repair activity (PMID: 29394989, 35736817, 35665744, 29884841, 33293522); Observed in an individual with breast cancer (PMID: 31786208); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 8015G>A; This variant is associated with the following publications: (PMID: 29394989, 30415210, 36243179, 29884841, 33609447, 12228710, 35736817, 35665744, 33293522, 35150867, 31409081, 31786208)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045321	SCV001209162	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989). 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. ClinVar contains an entry for this variant (Variation ID: 421439). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2596 of the BRCA2 protein (p.Gly2596Glu).
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001045321	SCV001478288	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-11-18	criteria provided, single submitter	curation	Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted to be deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (24.4) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.995 and an overall classification of pathogenic (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar as Uncertain Significance.
Ambry Genetics	RCV004023150	SCV005030055	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-13	criteria provided, single submitter	clinical testing	The p.G2596E variant (also known as c.7787G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7787. The glycine at codon 2596 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in two Czech patients referred for BRCA1/2 testing (Machackova E et al. Klin Onkol, 2019;32:51-71). A homology-directed DNA repair (HDR) assay demonstrated p.G2596E to have low functionality, with a probability of pathogenicity of 1.000 and a probability of neutrality of 1.73x10-5 (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). Another study found this variant to be likely benign based on multifactorial analysis which was largely driven by a co-occurrence likelihood ratio based on work by Easton et al (Lee JS et al. J. Med. Genet., 2018 12;55:794-802). The Easton multifactorial model considers a strong odds against pathogenicity for variants identified in a compound heterozygous state in individuals without biallelic disease (Easton DF et al. Am. J. Hum. Genet., 2007 Nov;81:873-83). The co-occurrence reported in Lee et al is with a pathogenic BRCA1 variant and is considered double heterozygosity rather than compound heterozygosity (Lee JS et al. J. Med. Genet., 2018 12;55:794-802; Personal communication). Double heterozygous carriers, although rare, are not appreciably different than those carrying a single pathogenic mutation in BRCA1 or BRCA2 (Vietri MT et al. Clin. Chem. Lab. Med., 2013 Dec;51:2319-24; Heidemann S et al. Breast Cancer Res. Treat., 2012 Aug;134:1229-39; Tsongalis GJ et al. Arch. Pathol. Lab. Med., 1998 Jun;122:548-50). 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.