ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1538A>G (p.Lys513Arg) (rs28897709)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112931 SCV000244422 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000189
GeneDx RCV000168549 SCV000210562 likely benign not specified 2017-07-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768620 SCV000219302 benign Breast and/or ovarian cancer 2017-08-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000215079 SCV000275310 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as 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.
Invitae RCV001082854 SCV000283171 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000112931 SCV000488971 benign Breast-ovarian cancer, familial 2 2016-07-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000215079 SCV000688711 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168549 SCV000694543 likely benign not specified 2019-05-07 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1538A>G (p.Lys513Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 234592 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1538A>G, has been reported in the literature in individuals affected with breast cancer (Lee_2008, Spurdle_2008, Loughrey_2008) and other tumor phenotypes (Kote-Jarai_2011, Young_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with another pathogenic variant have been reported (BRCA1 c.1961delA, p.Lys654SerfsX47; Spurdle_2008), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton_2007 and Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign (n=3), Benign (n=3 including the expert panel)). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000230296 SCV001133682 likely benign not provided 2018-12-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000168549 SCV001159053 likely benign not specified 2018-10-10 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000112931 SCV000145883 uncertain significance Breast-ovarian cancer, familial 2 2011-10-19 no assertion criteria provided clinical testing

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