ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.651dup (p.Lys218Ter) (rs63750955)

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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 RCV000202569 SCV000213905 pathogenic Hereditary cancer-predisposing syndrome 2018-01-09 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 RCV000202569 SCV000685513 pathogenic Hereditary cancer-predisposing syndrome 2016-12-13 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009487 SCV000744289 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075018 SCV000592572 pathogenic Lynch syndrome 2012-11-09 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009487 SCV000734212 pathogenic Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
GeneDx RCV000235180 SCV000149347 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing This duplication of one nucleotide is denoted MSH6 c.651dupT at the cDNA level and p.Lys218Ter (K218X) at the protein level. The normal sequence, with the base that is duplicated in brackets, is CAGA[T]AAGA. The duplication creates a nonsense variant, which changes a Lysine to a premature stop codon. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH6 c.651dupT, previously reported as 217insT, 650insT, and 651_652insT, has been observed in multiple individuals with suspected Lynch syndrome, with tumors showing absent MSH6 on immunohistochemistry, and was shown to segregate with disease in several families (Wu 1999, Plaschke 2000, Wu 2001, Berends 2002, Berends 2004, Hendriks 2004, Domingo 2005, Kets 2006, Overbeek 2007, Ramsoekh 2008, Steinke 2008, Ou 2009, van der Post 2010). MSH6 c.651dupT is considered pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075018 SCV000695923 pathogenic Lynch syndrome 2016-11-08 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075018 SCV000108239 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524211 SCV000283853 pathogenic Hereditary nonpolyposis colon cancer 2018-11-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys218*) in the MSH6 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 individuals with colorectal cancer and Lynch syndrome (PMID: 10521294, 2059188, 20028993, 17453009, 18625694). This variant is also known as 217insT in the literature. ClinVar contains an entry for this variant (Variation ID: 8932). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009487 SCV000029705 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2001-10-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235180 SCV000888295 pathogenic not provided 2015-09-10 criteria provided, single submitter clinical testing

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