ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8378G>A (p.Gly2793Glu) (rs80359083)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045500 SCV000073513 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 2793 of the BRCA2 protein (p.Gly2793Glu). 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 individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 38157). This variant has been reported to affect BRCA2 protein function (PMID: 23108138, 29394989, 29884841). This variant disrupts the p.Gly2793 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12442275, 15889636, 16030099, 19043619, 23233716, 23108138, 25085752, 25777348). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000165807 SCV000216554 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing The p.G2793E variant (also known as c.8378G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8378. The glycine at codon 2793 is replaced by glutamic acid, an amino acid with similar properties. This alteration was found to produce exon 19 skipping, however, the majority of transcript produced by this alteration is wildtype (Acedo A et al. Breast Cancer Res. 2012 May;14:R87). This amino acid substitution was shown to be defective in a homology directed repair assays (Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). Based on internal structural analysis, this alteration is predicted to disrupt binding to DSS1 and is more destabilizing to the local structure than other known pathogenic variants (Ambry internal data). 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.
Color Health, Inc RCV000165807 SCV000689121 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-05 criteria provided, single submitter clinical testing This missense variant replaces glycine with glutamic acid at codon 2793 of the BRCA2 protein. Computational prediction tool 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 resulted in impaired DNA repair (PMID: 23108138, 29394989) and abnormal splicing (PMID: 22632462). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 12442275, 23233716, 25777348; Lovejoy 2018; ClinVar ID: SCV001429660, internal data). Another variant at this amino acid (Gly2793Arg) has been classified as pathogenic (ClinVar Variant ID: 52569). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
PreventionGenetics,PreventionGenetics RCV000679191 SCV000805777 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045500 SCV001429660 pathogenic Hereditary breast and ovarian cancer syndrome 2019-02-14 criteria provided, single submitter clinical testing Data used in classification: Case control comparison of UK familial cases against ethnically matched population data (5/25,773 in familial UK cases against 0/56,856 GNOMAD NFE controls) 2-sided Fishers exact: pexact= 0.0030 (PS4_strong). Absent in the remainder of the gnomAD population (PM2_mod). This variant is predicted deleterious on AlignGVGD (class:C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging), CADD (29.8), Revel [0-1]: 0.916, Gavin class: Pathogenic, (confidence: genomewide) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay DNA Binding Domain assay (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of P=1.0 (PS3_strong). Data not used in classification: There are additional reports of this variant in ClinVar (5), DMuDB (1), BIC(4), and BRCA2 LOVD(1). 5 Classifications on ClinVar as uncertain. Ambry classification: likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679191 SCV001469720 uncertain significance not provided 2019-10-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031740 SCV000054347 uncertain significance Breast-ovarian cancer, familial 2 2010-07-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031740 SCV000147350 uncertain significance Breast-ovarian cancer, familial 2 2000-07-07 no assertion criteria provided clinical testing

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