ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2061T>A (p.Cys687Ter) (rs267608068)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074710 SCV000107917 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000162397 SCV000212720 pathogenic Hereditary cancer-predisposing syndrome 2019-11-19 criteria provided, single submitter clinical testing The p.C687* pathogenic mutation (also known as c.2061T>A), located in coding exon 4 of the MSH6 gene, results from a T to A substitution at nucleotide position 2061. This changes the amino acid from a cystine to a stop codon within coding exon 4. In one study, this mutation was reported in an individual from Scotland who was diagnosed with colorectal cancer prior to 55 years of age (Baglietto L et al. J Natl Cancer Inst. 2010 Feb 3;102(3):193-201). 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.
GeneDx RCV000201965 SCV000490620 pathogenic not provided 2017-10-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.2061T>A at the cDNA level and p.Cys687Ter (C687X) atthe protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon(TGT>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 an individual with a tubular adenoma and in a Scottish familywith multiple cases of colorectal or Lynch syndrome cancers (Pino 2009, Baglietto 2010), and is consideredpathogenic.
Invitae RCV000530716 SCV000624721 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-10-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys687*) 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 an individual affected with Lynch syndrome (PMID: 19324997). ClinVar contains an entry for this variant (Variation ID: 89246). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000162397 SCV000685252 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000201965 SCV000257218 likely pathogenic not provided no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353419 SCV000592595 pathogenic Endometrial carcinoma no assertion criteria provided clinical testing The p.Cys687X variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), COSMIC, Mismatch Repair Genes Variant, “MMR Gene Unclassified Variants, Zhejiang Colon Cancer, GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) databases. The variant was identified in dbSNP (ID: rs 267608068 “With Pathogenic allele”, in InSiGHT Colon Cancer Database (2x classified as pathogenic), in Clinvitae (2x classified as pathogenic), in LOVD as unknown. In the ClinVar database, the variant is classified as a pathogenic variant by InSIGHT and Ambry Genetics. The p.Cys687X variant leads to a premature stop codon at position 687, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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