Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491256 | SCV000580165 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-12-12 | criteria provided, single submitter | clinical testing | Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) |
| Invitae | RCV000704103 | SCV000833037 | pathogenic | Hereditary nonpolyposis colon cancer | 2018-03-04 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the MSH6 gene (p.Ala1320Glnfs*7). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acids of the MSH6 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 428325). A different truncation downstream of this variant (p.Leu1330Valfs*12), is a known Lynch syndrome founder mutation in the Ashkenazi Jewish population (PMID: 19851887, 21155762). This variant has been shown to abolish MSH6 expression and cause tumor microsatellite instability (PMID: 19851887). It has also been reported in individuals affected with constitutional mismatch repair deficiency syndrome (PMID: 24440087), and segregated with disease in a family affected with colorectal cancer (PMID: 14520694). This suggests that deletion of this region of the MSH6 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |