ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.25C>G (p.Leu9Val)

dbSNP: rs1672231681
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001323925 SCV001514860 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2021-09-02 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 9 of the MSH2 protein (p.Leu9Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. 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 MSH2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Baylor Genetics RCV004570786 SCV005053504 uncertain significance Lynch syndrome 1 2023-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV004945011 SCV005450594 likely benign Hereditary cancer-predisposing syndrome 2024-08-23 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.

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