ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.229T>C (p.Cys77Arg) (rs63749859)

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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) RCV000075596 SCV000106593 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000220766 SCV000274513 pathogenic Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Good segregation with disease (lod 1.5-3 = 5-9 meioses);Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position
Integrated Genetics/Laboratory Corporation of America RCV001192575 SCV001360803 pathogenic Hereditary nonpolyposis colon cancer 2019-01-22 criteria provided, single submitter clinical testing Variant summary: MLH1 c.229T>C (p.Cys77Arg) results in a non-conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain (IPR003594) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246190 control chromosomes (gnomAD). c.229T>C has been reported in the literature in multiple individuals affected with Lynch Syndrome, where the variant segregated with the disease (Panariello 1998, Nystrom-Lahti 2002). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating preserved interaction with PMS2, but deficient MMR function (Nystrom-Lahti 2002, Raevaara 2005, Borras 2012). In addition, based on a multifactorial likelihood analysis, the variant of interest was classified as pathogenic (Thompson 2014). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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