Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002354330 | SCV002623364 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-04 | criteria provided, single submitter | clinical testing | The c.3814delT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 3814, causing a translational frameshift with a predicted alternate stop codon (p.S1272Qfs*16). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). In a large (n=1591) series of patients referred for APC testing, this alteration was detected in one individual (Kerr SE et al. J Mol Diagn. 2013 Jan;15:31-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV003335130 | SCV004044923 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-09 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Invitae | RCV003335130 | SCV004292814 | pathogenic | Familial adenomatous polyposis 1 | 2023-09-05 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 156479). This premature translational stop signal has been observed in individual(s) with a personal or family history of APC-related conditions (PMID: 23159591). This sequence change creates a premature translational stop signal (p.Ser1272Glnfs*16) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1572 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). |
| Pathway Genomics | RCV000144569 | SCV000189862 | pathogenic | Familial adenomatous polyposis 1 | 2014-07-24 | no assertion criteria provided | clinical testing |