Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076498 | SCV000107527 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation introducing premature termination codon |
Gene |
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, |
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. |