Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003535941 | SCV000943556 | pathogenic | Familial adenomatous polyposis 1 | 2021-09-19 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with APC-related conditions. 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. 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 648862). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser2601Argfs*17) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 243 amino acid(s) of the APC protein. |
| Color Diagnostics, |
RCV001805871 | SCV002053499 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2022-01-02 | criteria provided, single submitter | clinical testing | This variant deletes 5 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to delete the EB1 and HDLG binding domains. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| Ambry Genetics | RCV001805871 | SCV003866266 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-26 | criteria provided, single submitter | clinical testing | The c.7803_7807delTAAAG variant, located in coding exon 15 of the APC gene, results from a deletion of 5 nucleotides at nucleotide positions 7803 to 7807, causing a translational frameshift with a predicted alternate stop codon (p.S2601Rfs*17). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 244 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 majority of available evidence to date, this variant is likely to be pathogenic. |