ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.112A>C (p.Asn38His) (rs63750580)

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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) RCV000075115 SCV000106106 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000129232 SCV000183987 pathogenic Hereditary cancer-predisposing syndrome 2014-02-13 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Other strong data supporting pathogenic classification
Invitae RCV001034681 SCV000284006 pathogenic Hereditary nonpolyposis colon cancer 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 38 of the MLH1 protein (p.Asn38His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This variant was reported in an individual with hereditary non-polyposis colon cancer (HNPCC) (PMID: 12373605) and was reported to segregate with HNPCC in 6 families (PMID: 20704743). ClinVar contains an entry for this variant (Variation ID: 89645). Experimental studies have shown that this variant reduces the functional activity and expression of the MLH1 protein (PMID: 20020535, 23403630). Additionally, based on a multifactorial likelihood algorithm using genetic, functional, and in silico data, this variant has been determined to have a high probability of being pathogenic (PMID: 22949379). For these reasons, this variant has been classified as Pathogenic.

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