Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000560222 | SCV000625396 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2017-08-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change results in a premature translational stop signal in the MSH2 gene (p.Tyr863Ilefs*2). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 72 amino acids of the MSH2 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. This variant is expected to disrupt nearly the entire C-terminal portion of the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain (disrupted residues Tyr863-Thr934) (PMID: 9774676, 18822302, 17531815). Although functional studies have not been done for this particular variant, loss of the C-terminal region of the protein likely impairs MSH2 function (PMID: 9774676, 18822302, 17531815). This suggests that deletion of this region of the MSH2 protein is causative of disease. |
| Ambry Genetics | RCV002431521 | SCV002743959 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-07-02 | criteria provided, single submitter | clinical testing | The c.2585dupG pathogenic mutation, located in coding exon 15 of the MSH2 gene, results from a duplication of G at nucleotide position 2585, causing a translational frameshift with a predicted alternate stop codon (p.Y863Ifs*2). This alteration occurs at the 3' terminus of theMSH2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 72 amino acids of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected and other pathogenic truncating mutations have been reported downstream of this alteration in patients with a personal and/or family history of HNPCC/Lynch syndrome (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |