ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1890T>G (p.Ile630Met) (rs774878438)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000580288 SCV000684779 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Invitae RCV000629929 SCV000750885 uncertain significance Hereditary nonpolyposis colon cancer 2017-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 630 of the MLH1 protein (p.Ile630Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs774878438, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000781544 SCV000919664 uncertain significance not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1890T>G (p.Ile630Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1890T>G, has been reported in the literature in individuals affected with Rhabdosarcoma (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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