ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1210C>A (p.Leu404Met) (rs1057517538)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573561 SCV000676058 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000808793 SCV000948914 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with methionine at codon 404 of the MLH1 protein (p.Leu404Met). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 486862). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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