ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8377G>A (p.Gly2793Arg)

gnomAD frequency: 0.00001  dbSNP: rs80359082
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045499 SCV000073512 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-25 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2793 of the BRCA2 protein (p.Gly2793Arg). This variant is present in population databases (rs80359082, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 12442275, 15889636, 16030099, 23233716, 25777348). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52569). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000074556 SCV000108641 pathogenic not provided 2021-11-09 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: significantly reduced homologous recombination DNA-repair activity and inability to rescue cell lethality in an embryonic stem cell assay (Guidugli 2013, Guidugli 2018, Hart 2019, Biswas 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 8605G>A; This variant is associated with the following publications: (PMID: 15889636, 29446198, 24323938, 25085752, 23233716, 19043619, 25777348, 16030099, 12442275, 29394989, 29997359, 28127413, 29922827, 30630528, 31331294, 30728895, 30264118, 26580448, 33293522, 29884841, 23108138, 33609447, 12228710)
Ambry Genetics RCV000131353 SCV000186328 pathogenic Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing The p.G2793R pathogenic mutation (also known as c.8377G>A), located in coding exon 18 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8377. The glycine at codon 2793 is replaced by arginine, an amino acid with dissimilar properties. <span style="background-color:initial">This alteration is located in the DNA binding domain (DBD) of BRCA2<span style="background-color:initial"> and was classified as pathogenic (p &ge; <span style="background-color:initial">0.999) by a highly sensitive and specific model based on in vivo<span style="background-color:initial"> homology-directed repair (HDR) activity (Guidugli L et al. Cancer Res.<span style="background-color:initial"> 2013 Jan 1;73(1):265-75l; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan;<span style="background-color:initial">). In addition, this alteration was predicted to be likely deleterious based on a computational method that produces a probabilistic likelihood ratio predictive of whether a missense variant impairs protein function (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). This alteration was detected in a woman of Mexican descent diagnosed with breast cancer at age 31 and was reported as a deleterious mutation detected in four Mexican families meeting NCCN guidelines for BRCA1/2<span style="background-color:initial"> testing (<span style="background-color:initial">Ruiz-Flores P et al. Hum Mutat. 2002 Dec;20(6):474-5; <span style="background-color:initial">Weitzel J et al. J. Clin. Oncol.<span style="background-color:initial"> 2013 Jan;31(2):210-6). 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 available evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077437 SCV000327881 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074556 SCV000600799 pathogenic not provided 2021-02-26 criteria provided, single submitter clinical testing This variant has been identified in individuals with breast cancer and breast/ovarian cancer families (PMID: 12442275 (2002), 15889636 (2005), 23233716 (2013), 25777348 (2015), and 31331294 (2019)). In addition, functional studies have shown that this variant greatly reduces the homology-directed DNA repair (HDR) activity of the BRCA2 protein (PMID: 23108138 (2013)). Furthermore, a multifactorial study reports that this variant is strongly associated with disease in families with a history of breast cancer (PMID: 25085752 (2014)). Variant is located in potentially critical domain of the protein. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Based on the available information, this variant is classified as pathogenic.
Counsyl RCV000077437 SCV000677700 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-07-31 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
Color Health, Inc RCV000131353 SCV000683961 pathogenic Hereditary cancer-predisposing syndrome 2021-05-20 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 2793 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 reported this variant to impact BRCA1 function in homology-mediated repair assay and in the rescue of Brca2-deficient mouse embryonic stem cells (PMID: 23108138, 29394989, 33293522). This variant has been detected in at least five individuals affected with high-risk breast cancer (PMID: 12442275, 25777348, 31331294; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 16030099, 23233716). This variant has been identified in 2/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
GeneKor MSA RCV000074556 SCV000693548 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Glycine for Arginine at codon 2793 of the BRCA2 protein. The glycine residue is highly conserved in a functional domain of the protein and there is a big physiochemical difference between glycine and arginine. This variant has been observed in 4 families affected with breast and/or ovarian cancer. Algorithms developed to predict the effect of missense changes on protein structure and functions suggest that this variant is likely to be detrimental to protein function. Experimental studies have shown that this missense change results in homology-directed repair activity comparable to known pathogenic mutations.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045499 SCV000695147 pathogenic Hereditary breast ovarian cancer syndrome 2020-11-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8377G>A (p.Gly2793Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) 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 8e-06 in 251552 control chromosomes. c.8377G>A has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018, Calderon-Garciduenas_2005, Ruiz-Flores_2002, Weitzel_2013, ElSaghir_2015). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired HDR (homology directed repair) activity (example, Guidugli_2013). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=7)/likely pathogenic(n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045499 SCV001478305 likely pathogenic Hereditary breast ovarian cancer syndrome 2018-10-09 criteria provided, single submitter curation Data used in classification: This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (31) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified as pathogenic by 8 submitters on ClinVar, including accredited USA laboratories GeneDx (2017) and Ambry Genetics (2016) (PP5_sup). This variant is at the same codon as a variant classified by CanVIG-UK as Pathogenic (c.8377G>A p.Gly2793Glu). (PP5_mod). Data not used in classification: The frequency of this variant is 2/123,101 individuals (the GNOMAD population). There are additional reports of this variant in BIC(4), and BRCA2 LOVD(1).
Mayo Clinic Laboratories,Mayo Clinic RCV000074556 SCV001714436 pathogenic not provided 2019-11-03 criteria provided, single submitter clinical testing PS3, PS4_Mod, PM2, PP3, PP5
Sharing Clinical Reports Project (SCRP) RCV000077437 SCV000109235 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-08-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077437 SCV000147349 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided 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

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