ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2536C>T (p.Gln846Ter)

dbSNP: rs63750857
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076498 SCV000107527 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
GeneDx RCV000657648 SCV000779395 pathogenic not provided 2017-10-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2536C>T at the cDNA level and p.Gln846Ter (Q846X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 individuals with Lynch syndrome (Mangold 2005, De Lellis 2013) and is considered pathogenic.
Invitae RCV001207810 SCV001379177 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-07-24 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant has been reported in individuals affected with hereditary nonpolyposis colorectal cancer (PMID: 15849733, 24278394). ClinVar contains an entry for this variant (Variation ID: 90996). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln846*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics RCV002453388 SCV002739310 pathogenic Hereditary cancer-predisposing syndrome 2023-10-13 criteria provided, single submitter clinical testing The p.Q846* pathogenic mutation (also known as c.2536C>T), located in coding exon 15 of the MSH2 gene, results from a C to T substitution at nucleotide position 2536. This changes the amino acid from a glutamine to a stop codon within coding exon 15. In a study of 1,721 German probands suspected of HNPCC, this mutation was detected in one family (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702). This mutation was also detected in 1/132 unrelated individuals who met either Amsterdam I or Amsterdam II criteria (De Lellis L et al. PLoS ONE 2013 Nov;8:e81194). This mutation was also reported in an MSH2-deficient colon tumor in conjunction with MSH2 loss of heterozygosity (Mensenkamp AR et al. Gastroenterology 2014 Mar;146:643-646.e8). Of note, this alteration is also designated as p.Gln846X and p.Gln846* in published literature. 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.
Myriad Genetics, Inc. RCV003452918 SCV004188080 pathogenic Lynch syndrome 1 2023-08-09 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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