ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8377G>A (p.Gly2793Arg) (rs80359082)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131353 SCV000186328 pathogenic Hereditary cancer-predisposing syndrome 2017-11-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Structural Evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077437 SCV000147349 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000131353 SCV000683961 pathogenic Hereditary cancer-predisposing syndrome 2016-11-24 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077437 SCV000327881 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077437 SCV000677700 likely pathogenic Breast-ovarian cancer, familial 2 2015-07-31 criteria provided, single submitter clinical testing
GeneDx RCV000074556 SCV000108641 pathogenic not provided 2018-11-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8377G>A at the cDNA level, p.Gly2793Arg (G2793R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 8605G>A. This variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (Ruiz-Flores 2002, Weitzel 2013, El Saghir 2015), and a homology-directed DNA break repair assay demonstrated that this variant results in significantly reduced homologous recombination repair activity (Guidugli 2013). BRCA2 Gly2793Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Gly2793Arg is located within the DSS1 contacting residues of the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider BRCA2 Gly2793Arg to be a pathogenic variant.
GeneKor MSA RCV000074556 SCV000693548 likely pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131353 SCV000679726 pathogenic Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045499 SCV000695147 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-15 criteria provided, single submitter clinical testing Variant Summary: The variant affects a conserved nucleotide and results in a replacement of a well-conserved non-polar glycine Glycine (G) with a polar Arginine (R) resulting in a non-conservative substitution. 5/5 in silico prediction tools predict deleterious outcome by this change. The variant was found in the broad and large cohort of the ExAc project at an allele frequency of 0.0082% which does not exceed the maximal expected allele frequency of a pathogenic BRCA2 variant (0.075%) further supporting a pathogenic outcome. The variant has been cited in multiple early onset breast cancer patients of Hispanic origin in the literature, however detailed information about the clinical presentation of the patients, their family history, co-segregation and co-occurrence with other deleterious alleles were not provided in these patient reports; An in vitro functional study showed that the variant impairs the loss of homologous recombination activity of BRCA2 as much as a pathogenic variant D2723H does, implicating a disease causing impact. Reputable databases and cinical diagnostic centers classify the variant as Likely Pathogenic/Pathogenic. Taken together, this variant has been classified as a Likely Pathogenic variant.
Invitae RCV000045499 SCV000073512 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2793 of the BRCA2 protein (p.Gly2793Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs80359082, ExAC 0.009%). This variant has been reported in individuals affected with breast cancer, frequently in Hispanic populations (PMID: 12442275, 15889636, 16030099, 23233716, 25777348). ClinVar contains an entry for this variant (Variation ID: 52569). Experimental studies have shown that this missense change disrupts BRCA2 homology-directed DNA break repair activity in cultured cells (PMID: 23108138). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 25085752). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074556 SCV000600799 pathogenic not provided 2017-01-06 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496849 SCV000587952 uncertain significance not specified 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077437 SCV000109235 pathogenic Breast-ovarian cancer, familial 2 2012-08-02 no assertion criteria provided clinical testing

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