ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.113A>G (p.Asn38Ser) (rs587778888)

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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) RCV000075118 SCV000106109 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000688444 SCV000816054 pathogenic Hereditary nonpolyposis colon cancer 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 38 of the MLH1 protein (p.Asn38Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Lynch syndrome in a family (PMID: 26895986). It has also been reported in an individual affected with Lynch syndrome (PMID: 15713769). ClinVar contains an entry for this variant (Variation ID: 89648). Experimental studies have shown that this missense change demonstrated loss of MMR function in human-yeast hybrid assay (PMID: 15475387). 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) A different missense substitution at this codon (p.Asn38His) has been determined to be pathogenic (PMID: 20704743, 12373605, 20020535, 23403630). This suggests that the asparagine residue is critical for MLH1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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