ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8435G>A (p.Gly2812Glu) (rs80359091)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045517 SCV000073530 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 2812 of the BRCA2 protein (p.Gly2812Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer and in an unaffected control (PMID: 25452441, 28283652). ClinVar contains an entry for this variant (Variation ID: 52586 ). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the BRCA2 gene (PMID: 19043619), suggest that this missense change is likely to be disruptive. However, experimental studies testing the effect of this missense change on homology-directed repair activity are currently inconclusive (PMID: 23108138, 29884841, 29394989). 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 2020-03-04 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. Using a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function, this alteration was classified as likely deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). In a functional study assessing unclassified variants using a cell-based homology-directed repair assay to determine pathogenicity, this alteration remained unclassified (Guidugli L et al. Cancer Res. 2013 Jan;73(1):265-75). 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). This alteration was 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 limited 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 2 2016-04-21 criteria provided, single submitter clinical testing
GeneDx RCV000589787 SCV000329143 uncertain significance not provided 2018-09-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8435G>A at the cDNA level, p.Gly2812Glu (G2812E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant, also defined as BRCA2 8663G>A using alternate nomenclature, has been observed in individuals with breast cancer as well as at least one healthy control (Couch 2015, Shimelis 2017). BRCA2 Gly2812Glu was classified as a variant of uncertain clinical significance by a multifactorial likelihood model incorporating results from a homology-directed DNA break repair functional assay (Guidugli 2013, Guidugli 2018). This variant was not observed in large population cohorts (Lek 2016). BRCA2 Gly2812Glu is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Gly2812Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
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 Health, Inc RCV000131431 SCV000911690 likely benign Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000589787 SCV001714437 uncertain significance not provided 2019-06-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077439 SCV000109237 uncertain significance Breast-ovarian cancer, familial 2 2006-12-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077439 SCV000147363 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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