Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000298073 | SCV000330540 | pathogenic | not provided | 2016-05-13 | criteria provided, single submitter | clinical testing | The c.2395dupT pathogenic variant in the APC gene causes a frameshift starting with codon Tyrosine 799, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Tyr799LeufsX4. This pathogenic variant is predicted to cause loss of normal protein function through protein truncation. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, another pathogenic frameshift variant occurring at the same position (c.2395delT) has been observed at GeneDx. Although the c.2395dupT variant has not been previously reported to our knowledge, we consider it to be pathogenic. |
| Invitae | RCV003650566 | SCV001234625 | pathogenic | Familial adenomatous polyposis 1 | 2019-04-24 | criteria provided, single submitter | clinical testing | A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 280611). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Tyr799Leufs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2045 amino acids of the APC protein. |
| Department of Pathology and Laboratory Medicine, |
RCV000298073 | SCV001553317 | uncertain significance | not provided | no assertion criteria provided | clinical testing |