ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3767A>G (p.His1256Arg) (rs80358618)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575182 SCV000664785 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing The p.H1256R variant (also known as c.3767A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3767. The histidine at codon 1256 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000575182 SCV000906904 likely benign Hereditary cancer-predisposing syndrome 2017-11-30 criteria provided, single submitter clinical testing
Invitae RCV001298086 SCV001487128 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-02-07 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1256 of the BRCA2 protein (p.His1256Arg). 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). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 51520). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113217 SCV000146295 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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