ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1318G>A (p.Val440Met) (rs864622250)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204188 SCV000259855 uncertain significance Lynch syndrome 2015-08-08 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 440 of the MLH1 protein (p.Val440Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases and has not been published in the literature. The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. Additionally, 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 is a novel missense change that is not predicted to affect protein function or cause disease. However the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance.
Color RCV000774705 SCV000908628 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000774705 SCV001171230 likely benign Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification

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