ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1483C>T (rs587779212)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074659 SCV000107861 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000131420 SCV000186400 pathogenic Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1483. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been identified in multiple individuals/families with HNPCC/Lynch syndrome based on personal and family history (Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Dominguez-Valentin M et al. BMC Urol. 2016 Mar;16:15; Beggs AD et al. Breast J. Jan;19:193-5). This alteration has been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835) and in a cohort of Latin American patients suspected of having Lynch syndrome (Rossi BM et al. BMC Cancer. 2017 Sep;17:623). This alteration was also detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing. (Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000074659 SCV000266090 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000202276 SCV000279096 pathogenic not provided 2018-04-12 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1483C>T at the cDNA level and p.Arg495Ter (R495X) 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 observed in individuals with a personal and/or family history of Lynch syndrome associated cancers (Brinkman 2006, Sjursen 2010, Bonadona 2011, Beggs 2013, Carneiro da Silva 2015, Shirts 2016, Lagerstedt-Robinson 2016), and is considered pathogenic.
Invitae RCV000524112 SCV000551164 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg495*) 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 observed in individual(s) with clinical features of Lynch syndrome (PMID: 20587412, 21642682, 27601186, 26437257). ClinVar contains an entry for this variant (Variation ID: 89197). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202276 SCV000888241 pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000074659 SCV000914308 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Mayo Clinic Laboratories, Mayo Clinic RCV000202276 SCV000257212 likely pathogenic not provided no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353858 SCV000592586 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Arg495X variant has been reported in the HGMD, COSMIC, InSiGHT databases and once in the literature in 5 out of 1028 proband chromosomes in individuals with HNPCC. However, no controls were tested to establish the frequency of the variant in the general population (Sjursen 2010). The variant leads to a premature stop codon at position 495 which is predicted to cause premature truncation of the protein product. This is a loss of function DNA variant and loss of function the MSH6 gene is an established disease mechanism for Lynch syndrome. In summary, based on the above information, this variant is classified as pathogenic.
Gharavi Laboratory,Columbia University RCV000202276 SCV000809460 pathogenic not provided 2018-09-16 no assertion criteria provided research
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249984 SCV001423998 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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