ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3202C>T (p.Arg1068Ter) (rs63749843)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000201960 SCV000604284 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000160692 SCV000580090 pathogenic Hereditary cancer-predisposing syndrome 2017-04-12 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 RCV000160692 SCV000537682 pathogenic Hereditary cancer-predisposing syndrome 2015-12-02 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000607176 SCV000744295 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-05-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074817 SCV000592625 pathogenic Lynch syndrome 2015-04-13 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000607176 SCV000734217 pathogenic Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763497 SCV000894283 pathogenic Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000201960 SCV000211314 pathogenic not provided 2018-04-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3202C>T at the cDNA level and p.Arg1068Ter (R1068X) 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 individuals with personal and/or family histories of Lynch syndrome-associated cancers (Plaschke 2002, McIlvried 2010, Hinrichsen 2013, Goodfellow 2015, Morak 2017) and is considered pathogenic.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000607176 SCV000743212 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2014-10-08 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000607176 SCV000840012 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2018-01-30 criteria provided, single submitter clinical testing This c.3202C>T variant in the MSH6 gene has been reported in multiple rectal cancer, HNPCC and Lynch syndrome patients [PMID:18301448, 20028993, 24323032] while not observed in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidence, this c.3202C>T (p.Arg1068*) in the MSH6 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074817 SCV000917784 pathogenic Lynch syndrome 2018-12-12 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3202C>T (p.Arg1068X) 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. The variant was absent in 277070 control chromosomes. c.3202C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Baglietto_2010, Dudley_2018, Plaschke_2002, Steinke_2008, Talseth-Palmer_2010, Thodi_2010). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074817 SCV000108028 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524156 SCV000253778 pathogenic Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1068*) 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, endometrial cancer, pancreatic cancer, and renal cancer (PMID: 11807791, 24323032, 20379851, 18301448, 20028993). ClinVar contains an entry for this variant (Variation ID: 89352). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201960 SCV000257241 pathogenic not provided no assertion criteria provided research
Pathway Genomics RCV000172816 SCV000223782 pathogenic Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000201960 SCV000889487 pathogenic not provided 2017-09-06 criteria provided, single submitter clinical testing
Vantari Genetics RCV000160692 SCV000267056 pathogenic Hereditary cancer-predisposing syndrome 2015-10-28 criteria provided, single submitter clinical testing

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