ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1381A>T (p.Lys461Ter) (rs63750540)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030213 SCV000106177 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Integrated Genetics/Laboratory Corporation of America RCV000030213 SCV000052880 pathogenic Lynch syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Ambry Genetics RCV000132422 SCV000187515 pathogenic Hereditary cancer-predisposing syndrome 2017-09-29 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)
GeneDx RCV000202201 SCV000279082 pathogenic not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1381A>T at the cDNA level and p.Lys461Ter (K461X) at the protein level. The substitution creates a nonsense variant, which changes a Lysine to a premature stop codon (AAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. In addition, this variant has been demonstrated to cause a partial splicing defect, leading to skipping of exon 12 in some transcripts (Stella 2001, Lastella 2004). MLH1 Lys461Ter has been reported in multiple families meeting Amsterdam Criteria or Bethesda Guidelines for Lynch syndrome and has been described as a North American founder pathogenic variant (Syngal 1999, Stella 2001, Terdiman 2001, Mueller 2009). We consider this variant to be pathogenic.
Invitae RCV000524235 SCV000284017 pathogenic Hereditary nonpolyposis colon cancer 2018-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys461*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in families and individuals affected with Lynch syndrome (PMID: 12658575, 11585727, 9377556, 19690142, 10422993, 11208710). ClinVar contains an entry for this variant (Variation ID: 36540). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202201 SCV000601354 pathogenic not provided 2016-04-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000030213 SCV000711429 pathogenic Lynch syndrome 2016-12-08 criteria provided, single submitter clinical testing The p.Lys461X variant in MLH1 has been reported in at least 5 individuals with L ynch Syndrome (Kitaeva 1997, Sygnal 1999, Stella 2001, Wagner 2003, Mueller 2009 ) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 461 which is predicted to lead to a tru ncated or absent protein. Furthermore, this variant has been classified as Patho genic on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV 000106177.2). In summary, this variant meets criteria to be classified as pathog enic for Lynch Syndrome in an autosomal dominant manner based upon the predicted impact to the protein.
Center for Human Genetics, Inc RCV000659871 SCV000781756 pathogenic Lynch syndrome II 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763102 SCV000893644 pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202201 SCV000257051 pathogenic not provided no assertion criteria provided research

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