Submissions for variant NM_000059.4(BRCA2):c.8435G>A (p.Gly2812Glu)

gnomAD frequency: 0.00001  dbSNP: rs80359091

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045517	SCV000073530	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2812 of the BRCA2 protein (p.Gly2812Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441, 28283652). ClinVar contains an entry for this variant (Variation ID: 52586). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 23108138, 29394989, 29884841, 29988080). 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.
Ambry Genetics	RCV000131431	SCV000186412	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing	The p.G2812E variant (also known as c.8435G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8435. The glycine at codon 2812 is replaced by glutamic acid, an amino acid with similar properties. One study found this variant to be functionally sufficient in a BRCA2-null mouse embryonic stem cell complementation assay, a homology-directed repair (HDR) assay, and a cisplatin sensitivity assay (Mesman RLS et al. Genet Med, 2019 02;21:293-302). In another study, this variant was similar to wildtype in a HDR assay (Hart SN et al. Genet Med, 2019 01;21:71-80). Another HDR assay demonstrated p.G2812E to have intermediate functionality, with a probability of pathogenicity of 0.390 and a probability of neutrality of 0.610 (Guidugli L et al. Am J Hum Genet, 2018 02;102:233-248). In a different functional study assessing variants that may potentially affect splice sites, this alteration did not show splicing disruption (Acedo A et al. Breast Cancer Res. 2012 May;14(3):R87). In one large case-control study, this variant was detected in 1/42671 Caucasian breast cancer cases, 1/42164 Caucasian controls, 0/5795 Asian breast cancer cases, and 0/6624 Asian controls (Shimelis H et al. Cancer Res, 2017 06;77:2789-2799), and p.G2812E was also identified in a triple negative breast cancer cohort, unselected for family histories of breast or ovarian cancer, undergoing multi-gene panel testing (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077439	SCV000267819	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000589787	SCV000329143	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing	Observed in breast cancer cases as well as unaffected controls (Couch et al., 2015; Shimelis et al., 2017); Functional studies are inconclusive with respect to homology directed repair activity, cisplatin sensitivity, and ability to rescue cell lethality (Guidugli et al., 2013; Guidugli et al., 2018; Mesman et al., 2018; Hart et al., 2019; Richardson et al., 2021; Iversen et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8663G>A; This variant is associated with the following publications: (PMID: 25452441, 23108138, 29394989, 35665744, 29884841, 28283652, 29988080, 33609447, 12228710, 24323938, 22632462, 19043619, 32042831)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175371	SCV000695153	uncertain significance	not specified	2019-12-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8435G>A (p.Gly2812Glu) results in a non-conservative amino acid change located in the nucleic acid-binding, OB-fold domain of the protein (interPro) 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 2.9e-06 in 348960 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8435G>A has been reported in the literature in individuals affected with breast cancer as well as in health controls (Couch_2015, Shimelis_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.1929delG, p.Arg645GlufsX15 in UMD database; BRCA1 c.671-2A>G at our laboratory), providing supporting evidence for a benign role. HDR and DNA damage sensitivity assays showed this variant has partial effect on protein function and results in > 50% WT activity (Guidugli_2012, Hart_2018, Mesman_2018). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000131431	SCV000911690	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 2812 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant does not impact homology-directed DNA repair activity and complements Brca2-null mouse embryonic stem cells (PMID: 23108138, 29394989, 29988080, 33609447). This variant has been reported in individuals affected with breast cancer (PMID: 25452441). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000589787	SCV001714437	uncertain significance	not provided	2019-06-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004803914	SCV004846020	uncertain significance	BRCA2-related cancer predisposition	2024-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 2812 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant does not impact homology-directed DNA repair activity and complements Brca2-null mouse embryonic stem cells (PMID: 23108138, 29394989, 29988080, 33609447). This variant has been reported in two individuals affected with breast cancer (PMID: 25452441) and it has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000326). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 0.583 (based on reported log(LR) = -0.234684691) (PMID: 31853058). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589787	SCV005625319	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	The BRCA2 c.8435G>A (p.Gly2812Glu) variant has been reported in the published literature in individuals with breast cancer (PMID: 28283652 (2017), 25452441 (2015)). The variant has also been observed in reportedly healthy individuals (PMID: 28283652 (2017)). Functional studies demonstrated that this variant has an inconclusive effect on protein function (PMID: 33609447 (2021), 29394989 (2018), 29988080 (2018), 23108138 (2013)).The frequency of this variant in the general population, 0.0000066 (1/152168 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP)	RCV000077439	SCV000109237	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-12-21	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077439	SCV000147363	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing