Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076557 | SCV000107586 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
Invitae | RCV000804938 | SCV000944877 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2023-04-12 | criteria provided, single submitter | clinical testing | Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 91055). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln10*) in the MSH2 gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. |
Laboratory for Molecular Medicine, |
RCV000076557 | SCV000967751 | pathogenic | Lynch syndrome | 2017-12-05 | criteria provided, single submitter | clinical testing | The p.Gln10X variant in MSH2 has been reported in 1 individual with MSH2-associa ted cancer (Mangold 2005) and was absent from large population studies. This non sense variant leads to a premature termination codon at position 10, which is pr edicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH2 gene is an established disease mechanism in Lynch syndrome. In addit ion, this variant was classified as pathogenic on Sept 13, 2013 by the ClinGen-a pproved InSiGHT expert panel (ClinVar SCV000107586.2). In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon absence from controls and its predicted impact on th e protein. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PS4_Supporting. |
Myriad Genetics, |
RCV003452931 | SCV004186830 | pathogenic | Lynch syndrome 1 | 2023-07-26 | 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. |