ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2459A>G (p.Asp820Gly)

gnomAD frequency: 0.00002  dbSNP: rs80358511
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084667 SCV000072013 likely benign Hereditary breast ovarian cancer syndrome 2024-01-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130196 SCV000185033 likely benign Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000077279 SCV000488788 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2016-06-15 criteria provided, single submitter clinical testing
GeneDx RCV000044000 SCV000512346 likely benign not provided 2021-02-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21523855, 23929434, 24817641, 27803004, 10923033)
Color Diagnostics, LLC DBA Color Health RCV000130196 SCV000688758 likely benign Hereditary cancer-predisposing syndrome 2017-03-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000435008 SCV001362930 likely benign not specified 2022-10-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2459A>G (p.Asp820Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 242584 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2459A>G has been reported in the literature in an individual affected with pancreatic ductal adenocarcinoma, however a co-occurring pathogenic variant (PALB2 c.1725dupG, pSer576Glufs*2) have been also found in this patient (Boeck 2017), providing supporting evidence for a benign role. It has also been reported as a VUS in individuals undergoing testing for breast cancer (example, Akter_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four of these classified the variant as likely benign. Based on the evidence outlined above, no conclusive evidence supporting a pathogenic outcome has been ascertained over a time frame of 5 years since its original classification by our laboratory and all subsequent evidence seem to support a benign outcome. Therefore, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington RCV000130196 SCV003848337 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Preventiongenetics, part of Exact Sciences RCV003415788 SCV004108567 uncertain significance BRCA2-related condition 2022-10-27 criteria provided, single submitter clinical testing The BRCA2 c.2459A>G variant is predicted to result in the amino acid substitution p.Asp820Gly. This variant was reported in an individual with pancreatic ductal adenocarcinoma, however a pathogenic PALB2 c.1725dupG (p.Ser576Glufs*2) variant and an uncertain ATM c.1066-6T>G (intronic) variant were also reported in that individual (Boeck et al 2017. PubMed ID: 27803004). This variant is reported in 0.011% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32910951-A-G) and has conflicting interpretations regarding is pathogenicity in ClinVar, ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/51291/). While this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044000 SCV004219542 uncertain significance not provided 2023-03-08 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00011 (3/28276 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with pancreatic cancer (PMID: 27803004 (2017)), renal cell carcinoma (PMID: 29610387 (2018)), and breast cancer (PMID: 31477031 (2019)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected controls (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sharing Clinical Reports Project (SCRP) RCV000077279 SCV000109076 likely benign Breast-ovarian cancer, familial, susceptibility to, 2 2011-04-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077279 SCV000146052 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2001-02-16 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000044000 SCV001932220 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000044000 SCV001952525 likely benign not provided no assertion criteria provided clinical testing

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