ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4373A>G (p.His1458Arg) (rs587782185)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130812 SCV000185708 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000238654 SCV000487896 uncertain significance Breast-ovarian cancer, familial 2 2015-12-04 criteria provided, single submitter clinical testing
Invitae RCV000469193 SCV000549575 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-05-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1458 of the BRCA2 protein (p.His1458Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142023). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486756 SCV000569133 uncertain significance not provided 2018-02-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4373A>G at the cDNA level, p.His1458Arg (H1458R) 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 4601A>G. BRCA2 His1458Arg has been reported in an individual with prostate cancer (Hayano 2016). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 His1458Arg is located in the region of interaction with RAD51 and POLH (Buisson 2014, UniProt). 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 His1458Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000238654 SCV000297526 uncertain significance Breast-ovarian cancer, familial 2 2010-01-19 no assertion criteria provided clinical testing

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