Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV004562796 | SCV000960954 | pathogenic | Familial adenomatous polyposis 1 | 2018-07-24 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). 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. 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. This variant has not been reported in the literature in individuals with APC-related disease. This sequence change results in a premature translational stop signal in the APC gene (p.Ser2132*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 712 amino acids of the APC protein. |
| Ambry Genetics | RCV004659232 | SCV005153990 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-03-28 | criteria provided, single submitter | clinical testing | The p.S2132* pathogenic mutation (also known as c.6395C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 6395. This changes the amino acid from a serine to a stop codon within coding exon 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 25% 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 has been observed in at least one individual with a personal and/ or family history that is consistent with APC-associated polyposis conditions (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. |