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
Ambry Genetics RCV000562335 SCV000676013 pathogenic Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075598 SCV000592340 pathogenic Lynch syndrome 2015-05-06 criteria provided, single submitter clinical testing
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.

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