ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.382G>C (p.Ala128Pro)

dbSNP: rs63750866
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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) RCV000075687 SCV000106693 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Labcorp Genetics (formerly Invitae), Labcorp RCV005089510 SCV005834388 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-09-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 128 of the MLH1 protein (p.Ala128Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9218993). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90199). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or 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 affects MLH1 function (PMID: 12810663, 17135187, 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.

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