ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3514dup (p.Arg1172fs) (rs63751327)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166347 SCV000217134 pathogenic Hereditary cancer-predisposing syndrome 2018-02-26 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 RCV000166347 SCV000905457 pathogenic Hereditary cancer-predisposing syndrome 2018-04-11 criteria provided, single submitter clinical testing
Counsyl RCV000409599 SCV000488032 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-12-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074872 SCV000592646 pathogenic Lynch syndrome 2014-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000074872 SCV000917779 pathogenic Lynch syndrome 2018-10-19 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3514dupA (p.Arg1172LysfsX5) 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 allele was found at a frequency of 1.1e-05 in 277060 control chromosomes (gnomAD). c.3514dupA has been reported in the literature in multiple individuals affected with Lynch Syndrome or related tumor phenotypes (Nilbert 2009, Schofield 2009, Sjursen 2010, Steinke2008, Wijnen 1999, Plaschke 2004, Haraldsdottir 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. Three 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) RCV000074872 SCV000108084 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000627713 SCV000283809 pathogenic Hereditary nonpolyposis colon cancer 2018-11-29 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 6 of the MSH6 mRNA (c.3514dupA), causing a frameshift at codon 1172. This creates a premature translational stop signal (p.Arg1172Lysfs*5) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic. This particular variant has been reported in families with suspected Lynch syndrome (PMID: 10508506, 18566915, 20587412) and in individuals affected with urothelial, colorectal, bladder and ovarian cancer (PMID: 20591884, 20682701, 24728189, 19130300). This variant is also known as 1172insA or c.3514_3515insA in the literature. ClinVar contains an entry for this variant (Variation ID: 89404). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202194 SCV000257260 pathogenic not provided no assertion criteria provided research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202194 SCV000888277 pathogenic not provided 2015-10-08 criteria provided, single submitter clinical testing

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