Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003650742 | SCV001392635 | pathogenic | Familial adenomatous polyposis 1 | 2022-03-08 | 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: 949218). This variant has not been reported in the literature in individuals affected with APC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Pro2339Glnfs*15) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 505 amino acid(s) of the APC protein. |
| Ambry Genetics | RCV002365995 | SCV002665735 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-07-25 | criteria provided, single submitter | clinical testing | The c.7016_7076del61 pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 61 nucleotides at nucleotide positions 7016 to 7076, causing a translational frameshift with a predicted alternate stop codon (p.P2339Qfs*15). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 505 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Myriad Genetics, |
RCV002562510 | SCV004043506 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-16 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |