Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076331 | SCV000107355 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation introducing premature termination codon |
| Ambry Genetics | RCV002415554 | SCV002718524 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-25 | criteria provided, single submitter | clinical testing | The c.1986_1987delGA pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 1986 to 1987, causing a translational frameshift with a predicted alternate stop codon (p.Q662Hfs*13). This mutation, designated "del of 2 bp, AG, at nucleotide positions 1985 and 1986," was identified in a family with HNPCC that included individuals with colorectal, endometrial, small bowel, and transitional cell cancers of the bladder and ureter as well as Muir-Torre skin lesions (Kolodner RD et al. Genomics 1994 Dec;24:516-26). 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. |
| Department of Pathology and Laboratory Medicine, |
RCV001355785 | SCV001550767 | pathogenic | not provided | no assertion criteria provided | clinical testing | The MSH2 p.Gln662Hisfs*13 variant was identified in a large Muir-Torre syndrome family, that segregated with the disease in affected members (Kolodner 1994). The variant was also identified in dbSNP (ID: rs63749976) however the clinical significance was listed as “NA”. The variant was classified as pathogenic on Clinvitae, “Mismatch Repair Genes Variant Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), and ClinVar database (classification pathogenic) however each database entry was in reference to the family in the above Kolodner publication. The c.1986_1987delGA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 662 and leads to a premature stop codon 13 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 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. |