ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1244A>G (p.His415Arg) (rs80358417)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000160035 SCV000071779 likely benign not provided 2018-12-24 criteria provided, single submitter clinical testing
GeneDx RCV000160035 SCV000210265 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1244A>G at the cDNA level, p.His415Arg (H415R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Using alternate nomenclature, this variant would be defined as BRCA2 1472A>G. This variant has been identified in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Wong-Brown 2015, Alemar 2017). BRCA2 His415Arg was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 His415Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000165768 SCV000216513 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000112899 SCV000488424 uncertain significance Breast-ovarian cancer, familial 2 2016-03-23 criteria provided, single submitter clinical testing
Color RCV000165768 SCV000903093 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780016 SCV000917010 uncertain significance not specified 2018-08-03 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1244A>G (p.His415Arg) 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 1.8e-05 in 275910 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1244A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Wong-Brown 2015, Alemar 2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (UMD: BRCA1 c.3979C>T (p.Gln1327X)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112899 SCV000145839 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735440 SCV000863576 uncertain significance Breast and/or ovarian cancer 2014-01-29 no assertion criteria provided clinical testing

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