Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076499 | SCV000107528 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation introducing premature termination codon |
Invitae | RCV001854330 | SCV002223166 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-07-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the MSH2 protein in which other variant(s) (p.Leu888Cysfs*4) have been determined to be pathogenic (PMID: 8640829, 9222765, 9774676, 17531815, 18822302, 21879275). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90997). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu849Trpfs*43) in the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 86 amino acid(s) of the MSH2 protein. |
Ambry Genetics | RCV002426637 | SCV002742906 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-11-08 | criteria provided, single submitter | clinical testing | The c.2545delC variant, located in coding exon 15 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 2545, causing a translational frameshift with a predicted alternate stop codon (p.L849Wfs*43). This variant has been identified as somatic in conjunction with a germline pathogenic MSH2 variant in a tumor that demonstrated high microsatellite instability with loss of MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 9% of the protein. The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |