ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1524A>G (p.Ile508Met)

dbSNP: rs1593893119
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001012007 SCV001172406 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-04 criteria provided, single submitter clinical testing The p.I508M variant (also known as c.1524A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1524. The isoleucine at codon 508 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001233557 SCV001406158 uncertain significance Hereditary breast ovarian cancer syndrome 2019-07-17 criteria provided, single submitter clinical testing 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 conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This sequence change replaces isoleucine with methionine at codon 508 of the BRCA2 protein (p.Ile508Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine.
University of Washington Department of Laboratory Medicine, University of Washington RCV001012007 SCV003851456 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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