ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1942C>T (p.Pro648Ser) (rs63750899)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075432 SCV000106428 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000162472 SCV000212839 pathogenic Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Deficient protein function in appropriate functional assay(s)
Invitae RCV001040524 SCV001204103 pathogenic Hereditary nonpolyposis colon cancer 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 648 of the MLH1 protein (p.Pro648Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch Syndrome in families (PMID: 12112654, 15139004, 16724012). ClinVar contains an entry for this variant (Variation ID: 17097). This variant has been reported to affect MLH1 protein function (PMID: 15139004, 16724012, 21404117). This variant disrupts the p.Pro648 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16083711, 11726306, 21404117). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000018629 SCV000038912 pathogenic Lynch syndrome II 2004-07-01 no assertion criteria provided literature only
OMIM RCV000018630 SCV000038913 pathogenic Turcot syndrome 2004-07-01 no assertion criteria provided literature only

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