Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000467909 | SCV000548166 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-07-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys29*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 408478). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. |
| Laboratory for Molecular Medicine, |
RCV004017628 | SCV004848532 | likely pathogenic | Lynch syndrome | 2021-10-27 | criteria provided, single submitter | clinical testing | The p.Lys29X variant in MSH2 has not been previously reported in individuals with MSH2-related conditions but has been reported by other clinical laboratories in ClinVar (Variation ID: 408478). It is absent in large population studies. This nonsense variant leads to a premature termination codon at position 29, which is predicted to lead to a truncated or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. |
| Ambry Genetics | RCV004022693 | SCV005033698 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-11-16 | criteria provided, single submitter | clinical testing | The p.K29* pathogenic mutation (also known as c.85A>T), located in coding exon 1 of the MSH2 gene, results from an A to T substitution at nucleotide position 85. This changes the amino acid from a lysine to a stop codon within coding exon 1. This variant was reported in a 48 year old female proband diagnosed with rectal cancer that demonstrated absent MSH6 and MSH2 expression by immunohistochemistry (Yamada A et al. Mol Clin Oncol, 2021 Dec;15:247). 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. |