ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.332C>T (p.Ala111Val) (rs63750539)

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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) RCV000075658 SCV000106660 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000627728 SCV000543619 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-03-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 111 of the MLH1 protein (p.Ala111Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families affected with Lynch syndrome PMID: 10777691, 16451135, 11920650, 17510385, Invitae). ClinVar contains an entry for this variant (Variation ID: 90171) Based on a multifactorial likelihood algorithm using clinical and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this missense change disrupts MLH1 protein function based on yeast and in vitro MMR assays (PMID: 17510385). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353512 SCV000592352 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Ala111Val variant has been reported in the literature in 4/594 proband chromosomes from individuals with HNPCC or suspected HNPCC, all of whom met either the Amsterdam criteria II or modified HNPCC criteria. It was not reported in any of the 800 control chromosomes evaluated (Caldes 2002, Chao 2008, Kurzawski 2006, Nomura 2000, Takahashi 2007). In one of these studies, all colorectal tumors belonging to a family with the variant had microsatellite instability at one of the loci evaluated (Caldes 2002). In a functional study that examined the MMR repair ability of the variant, the mutant was found to be have severely compromised repair capacity compared to the wild-type (only 25%). MLH1 expression was found to be between 25-75% (Takahashi 2007). This variant is listed in the dbSNP database (ID#:rs28897759) as coming from a clinical source, but no frequency information was provided, and so the prevalence of this variant in the population is not known. It is not listed in the LOVD or UMD databases. The p.Ala111 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Ala111Val variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In addition, this individual was shown to have MLH1 deficient tumour by IHC, increasing the likelihood this variant may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic.

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