ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1470G>C (p.Met490Ile) (rs1060500708)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471108 SCV000543635 uncertain significance Lynch syndrome 2016-08-19 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 490 of the MLH1 protein (p.Met490Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MLH1-related disease. 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 novel 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.
Ambry Genetics RCV000565669 SCV000662105 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence

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