ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.371G>C (p.Cys124Ser)

dbSNP: rs730881736
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000805112 SCV000945056 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-10-04 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but 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 MLH1-related disease. This sequence change replaces cysteine with serine at codon 124 of the MLH1 protein (p.Cys124Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine.
All of Us Research Program, National Institutes of Health RCV004001675 SCV004841992 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces cysteine with serine at codon 124 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 MLH1-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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