ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1645G>A (p.Val549Ile)

gnomAD frequency: 0.00001  dbSNP: rs876659905
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218213 SCV000276845 likely benign Hereditary cancer-predisposing syndrome 2024-08-09 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000629673 SCV000750629 benign Hereditary nonpolyposis colorectal neoplasms 2024-10-20 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000218213 SCV001339978 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-24 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 549 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 been identified in 1/251230 chromosomes 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.
Baylor Genetics RCV003462501 SCV004196237 uncertain significance Lynch syndrome 1 2023-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004998472 SCV005623627 uncertain significance not provided 2024-11-29 criteria provided, single submitter clinical testing The MSH2 c.1645G>A (p.Val549Ile) variant has been identified in the published literature in in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). A screening assay based on cell survival in response to 6-thioguanine treatment indicates this variant has a neutral effect on DNA mismatch repair function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000004 (1/251230 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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