ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2722T>A (p.Leu908Ile)

dbSNP: rs1085308059
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
All of Us Research Program, National Institutes of Health RCV004016626 SCV004836825 uncertain significance Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces leucine with isoleucine at codon 908 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). To our knowledge, functional studies have not been reported for this variant. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV005103317 SCV005771554 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-03-30 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 908 of the MSH2 protein (p.Leu908Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. 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.

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