ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1064C>T (p.Pro355Leu) (rs587782467)

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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 RCV000131560 SCV000186564 uncertain significance Hereditary cancer-predisposing syndrome 2013-08-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000471422 SCV000543652 uncertain significance Hereditary nonpolyposis colon cancer 2017-03-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 355 of the MLH1 protein (p.Pro355Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs587782467, ExAC 0.006%) but has not been reported in the literature in individuals with an MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 142439). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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