ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5871A>G (p.Ile1957Met)

dbSNP: rs1566233369
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000702885 SCV000831757 uncertain significance Hereditary breast ovarian cancer syndrome 2019-12-30 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals with BRCA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 1957 of the BRCA2 protein (p.Ile1957Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine.
Ambry Genetics RCV002352197 SCV002647711 uncertain significance Hereditary cancer-predisposing syndrome 2022-05-13 criteria provided, single submitter clinical testing The p.I1957M variant (also known as c.5871A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5871. The isoleucine at codon 1957 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV002352197 SCV003850741 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).
All of Us Research Program, National Institutes of Health RCV004802391 SCV005424505 uncertain significance BRCA2-related cancer predisposition 2024-07-20 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 1957 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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