ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.62C>A (p.Ala21Glu) (rs63750706)

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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) RCV000075786 SCV000106796 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
Invitae RCV000811318 SCV000951578 likely pathogenic Hereditary nonpolyposis colon cancer 2019-02-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 21 of the MLH1 protein (p.Ala21Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with Lynch syndrome or constitutional mismatch repair deficiency (PMID: 21404117, 30013564). ClinVar contains an entry for this variant (Variation ID: 90297). Experimental studies have shown that this missense change retained PMS2 binding activity and some MLH1 protein function in yeast assays (PMID: 21404117). This variant disrupts the p.Ala21 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 14961575), which suggests that this may be a clinically significant amino acid residue. 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.

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