Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001026426 | SCV001188806 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-08-27 | criteria provided, single submitter | clinical testing | The c.742dupC pathogenic mutation, located in coding exon 4 of the MSH6 gene, results from a duplication of C at nucleotide position 742, causing a translational frameshift with a predicted alternate stop codon (p.R248Pfs*8). 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. |
| Invitae | RCV001873409 | SCV002149593 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-04-13 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 827041). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg248Profs*8) 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). |
| Myriad Genetics, |
RCV003455136 | SCV004185595 | pathogenic | Lynch syndrome 5 | 2023-08-10 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Laboratory for Molecular Medicine, |
RCV004017777 | SCV004847762 | likely pathogenic | Lynch syndrome | 2019-05-08 | criteria provided, single submitter | clinical testing | The p.Arg248ProfsX8 variant in MSH6 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 248 and leads to a premature termination codon 8 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 autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg248ProfsX8 variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1; PM2. |