ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.827T>G (p.Ile276Arg)

dbSNP: rs1253275403
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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) RCV000623903 SCV000740671 pathogenic Lynch syndrome 1 2018-03-09 reviewed by expert panel curation Class 5 - Pathogenic Classification using multifactorial probability: 0.997
Genetics and Molecular Pathology, SA Pathology RCV003447545 SCV004175568 likely pathogenic Lynch syndrome 2021-06-15 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003594010 SCV004312666 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-11-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 276 of the MLH1 protein (p.Ile276Arg). 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 (external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 520540). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MLH1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 36054288). For these reasons, this variant has been classified as Pathogenic.

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