ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.230G>A (p.Cys77Tyr) (rs63750437)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075598 SCV000106595 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000791362 SCV000543634 pathogenic Hereditary nonpolyposis colon cancer 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 77 of the MLH1 protein (p.Cys77Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs63750437, ExAC no frequency). This variant has been reported in individuals with hereditary non-polyposis colorectal cancer (PMID: 9032648, 15849733, 17510385, 21404117). ClinVar contains an entry for this variant (Variation ID: 90112). Experimental studies have shown that this variant disrupts protein interactions and reduces the mismatch repair activity and expression of the MLH1 protein (PMID: 22949387, 17510385, 12810663, 17210669, 17135187). Additionally, this variant has been determined to have a high probability of being pathogenic based on an algorithm developed specifically for the MLH1 gene and a multifactorial likelihood algorithm using genetic, functional, and in silico data (PMID: 18383312, 22949379). A different missense substitution at this codon (p.Cys77Arg) is reported to be deleterious (PMID: 11793442, 24362816, 18383312, 16083711). This indicates that the cysteine residue is important for MLH1 protein function. For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075598 SCV000592340 pathogenic Lynch syndrome 2015-05-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562335 SCV000676013 pathogenic Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000562335 SCV000689869 pathogenic Hereditary cancer-predisposing syndrome 2020-04-30 criteria provided, single submitter clinical testing

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