ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.676C>T (p.Arg226Ter) (rs63751615)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115485 SCV000212825 pathogenic Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000115485 SCV000689906 pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing
Counsyl RCV000018616 SCV000785381 pathogenic Lynch syndrome II 2017-07-19 criteria provided, single submitter clinical testing
GeneDx RCV000202205 SCV000149394 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.676C>T at the cDNA level and p.Arg226Ter (R226X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple families with Lynch syndrome and at least one patient with epithelial ovarian cancer (Moslein 1996, Castillejo 2011, Pal 2012, Lagerstedt-Robinson 2016). MLH1 Arg226Ter was also observed in the homozygous state in two siblings with constitutional mismatch repair-deficiency (CMMR-D) (Alotaibi 2008). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075801 SCV000917661 pathogenic Lynch syndrome 2018-08-14 criteria provided, single submitter clinical testing Variant summary: MLH1 c.676C>T (p.Arg226X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075801 SCV000106813 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524311 SCV000284071 pathogenic Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 226 (p.Arg226*). It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with disease in several families with Lynch syndrome (PMID: 8872463, 10874307, 15849733, 15655560, 17889038, 21247423, 24344984) and has also been found in an individual with ovarian cancer (PMID: 23047549). ClinVar contains an entry for this variant (Variation ID: 17087). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202205 SCV000257111 pathogenic not provided no assertion criteria provided research
OMIM RCV000018616 SCV000038899 pathogenic Lynch syndrome II 2001-05-01 no assertion criteria provided literature only
OMIM RCV000018617 SCV000038900 pathogenic Turcot syndrome 2001-05-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202205 SCV000601407 pathogenic not provided 2015-09-17 criteria provided, single submitter clinical testing

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