ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1507C>A (p.Leu503Ile)

dbSNP: rs1553365825
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002000697 SCV002267717 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-01-20 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with isoleucine at codon 503 of the MSH2 protein (p.Leu503Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine.
All of Us Research Program, National Institutes of Health RCV004011052 SCV004833485 uncertain significance Lynch syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 503 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-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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