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 RCV000075658 SCV000592352 likely pathogenic Lynch syndrome 2015-02-03 criteria provided, single submitter clinical testing

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