ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1538A>G (p.Lys513Arg) (rs28897709)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215079 SCV000275310 benign Hereditary cancer-predisposing syndrome 2014-11-19 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
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
Color RCV000215079 SCV000688711 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000112931 SCV000488971 benign Breast-ovarian cancer, familial 2 2016-07-27 criteria provided, single submitter clinical testing
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.
Integrated Genetics/Laboratory Corporation of America RCV000168549 SCV000694543 likely benign not specified 2019-05-07 criteria provided, single submitter clinical testing 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.
Invitae RCV000230296 SCV000283171 likely benign Hereditary breast and ovarian cancer syndrome 2017-11-17 criteria provided, single submitter clinical testing

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