ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1958T>G (p.Leu653Arg) (rs63751202)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075437 SCV000106433 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probability > 0.95 (0.990)
Invitae RCV001203288 SCV001374445 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 653 of the MLH1 protein (p.Leu653Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89957). This variant has been reported to affect MLH1 protein function (PMID: 17510385, 21952876, 17210669, 23403630). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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