ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6752A>G (p.His2251Arg)

dbSNP: rs1555284844
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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 RCV000510065 SCV000608174 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-30 criteria provided, single submitter clinical testing The p.H2251R variant (also known as c.6752A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6752. The histidine at codon 2251 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001775836 SCV002012681 uncertain significance not provided 2019-10-28 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 6980A>G
Labcorp Genetics (formerly Invitae), Labcorp RCV001857311 SCV002143004 uncertain significance Hereditary breast ovarian cancer syndrome 2023-12-16 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2251 of the BRCA2 protein (p.His2251Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 441472). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000510065 SCV003847424 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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