ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1649T>C (p.Leu550Pro) (rs63750193)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075292 SCV000106285 pathogenic Lynch syndrome I 2016-11-03 reviewed by expert panel research Segregation LR = 12.25. Abrogated function (reduced expression in 2 inpedendent assays) & 2 MSI-H tumours
Ambry Genetics RCV000570739 SCV000662040 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV001212034 SCV001383606 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 550 of the MLH1 protein (p.Leu550Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 21404117, 16083711, 16216036, Invitae). ClinVar contains an entry for this variant (Variation ID: 89818). This variant has been reported to affect MLH1 protein function (PMID: 16083711, 21404117, 22753075, 21120944, 18999873, 20020535). 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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