Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000646469 | SCV000768241 | pathogenic | Familial adenomatous polyposis 1 | 2017-09-15 | criteria provided, single submitter | clinical testing | This sequence change results in a premature translational stop signal in the APC gene (p.Asn1546Lysfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1298 amino acids (~46%) of the APC protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with familial adenomatous polyposis in a family (PMID: 15108286), and has also been observed in individuals with familial adenomatous polyposis (PMID: 1316610, 20685668, 21643010). This variant removes the final 1298 amino acids of the APC protein, including the basic domain, the EB1 binding site, and the HDLG binding site, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). Different truncations downstream of this variant, p.Tyr2645Lysfs*14 and p.Asp1942Glufs*27, have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 15108286, 11001924). While functional studies have not been performed to directly test the effect of this variant on APC protein function, these observations suggest that deletion of the C-terminal portion of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |