Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001801041 | SCV002046403 | pathogenic | not provided | 2020-11-10 | criteria provided, single submitter | clinical testing | This frameshift variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. It has been reported in a Lynch Syndrome family in the published literature (PMID: 20487569 (2016)). Based on the available information, the variant is classified as pathogenic. |
| Ambry Genetics | RCV002361061 | SCV002663614 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-03-19 | criteria provided, single submitter | clinical testing | The c.675_676dupTG variant, located in coding exon 4 of the MSH6 gene, results from a duplication of TG at nucleotide position 675, causing a translational frameshift with a predicted alternate stop codon (p.E226Vfs*21). This mutation has been reported in patients with early onset familial colon cancer/Lynch Syndrome (Talseth-Palmer BA et al. Hered Cancer Clin Pract, 2010 May;8:5; Chubb D et al. Nat Commun, 2016 06;7:11883). Of note, this alteration is also designated as c.674insTG and c.674_675insTG in the published 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. |
| Laboratory for Molecular Medicine, |
RCV004017870 | SCV004848289 | likely pathogenic | Lynch syndrome | 2019-10-14 | criteria provided, single submitter | clinical testing | The p.Glu226ValfsX21 variant in MSH6 has been reported in 1 individual with Lynch syndrome (as c.674insTG; Talseth-Palmer 2010) 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 226 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, the p.Glu226ValfsX21 variant meets criteria to be classified as pathogenic for Lynch syndrome. ACMG/AMP criteria applied: PVS1, PM2. |