ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1076T>C (p.Met359Thr) (rs779917781)

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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 RCV000221003 SCV000273577 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000688104 SCV000815704 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-04-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 359 of the MLH1 protein (p.Met359Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs779917781, ExAC 0.002%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 230138). 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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