Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003759035 | SCV004376556 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2023-04-23 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1088Leufs*4) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). ClinVar contains an entry for this variant (Variation ID: 973406). For these reasons, this variant has been classified as Pathogenic. |
| Laboratory for Molecular Medicine, |
RCV004017809 | SCV004848299 | likely pathogenic | Lynch syndrome | 2019-10-14 | criteria provided, single submitter | clinical testing | The p.Phe1088LeufsX4 variant in MSH6 has not been previously reported in individuals with Lynch Syndrome or in large large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome based upon the predicted impact to the protein and absence from the general population. ACMG/AMP criteria applied: PVS1, PM2. |
| Constitutional Genetics Lab, |
RCV001249971 | SCV001423985 | pathogenic | Lynch-like syndrome | 2019-07-01 | no assertion criteria provided | clinical testing |