ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1939G>A (p.Val647Met) (rs63750109)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130400 SCV000185260 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000629852 SCV000750808 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 647 of the MLH1 protein (p.Val647Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs63750109, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with prostate cancer, polyposis, or suspected Lynch syndrome (PMID: 16963262, 27696107, 27601186). ClinVar contains an entry for this variant (Variation ID: 89952). 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.
Color RCV000130400 SCV001344073 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing

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