ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131431 SCV000186412 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077439 SCV000147363 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000131431 SCV000911690 likely benign Hereditary cancer-predisposing syndrome 2016-01-20 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.
Integrated Genetics/Laboratory Corporation of America RCV000589787 SCV000695153 uncertain significance not provided 2017-07-17 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.8435G>A (p.Gly2812Glu) variant involves the alteration of a conserved nucleotide located in the Nucleic acid-binding, OB-fold domain of the protein (interPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/218962 control chromosomes at a frequency of 0.0000046, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in BrC patients without strong evidence for causality. A mega-study reported comparible MAF of variant in two case-control cohorts: 1/42671 Caucasian BrC cases and 1/42164 Caucasian controls, 0/5795 Asian BrC cases and 0/6624 Asian controls (Shimelis_BRCA1_CR_2017). HDR assay showed variant with > 50% WT activity (Guidugli_Cancer Res_2012). One internal sample also carried c.671-2A>G in BRCA1 that was classified as a VUS-possibly pathogenic variant due to equivocal evidence of an impact on splicing. UMD lists variant in three individuals with co-occurrence of BRCA2 c.1929delG/p.Arg645GlufsX15, supporting a non-pathogenic role for variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as a VUS until more evidence becomes available.
Invitae RCV000045517 SCV000073530 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-04 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.
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
Sharing Clinical Reports Project (SCRP) RCV000077439 SCV000109237 uncertain significance Breast-ovarian cancer, familial 2 2006-12-21 no assertion criteria provided clinical testing

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