Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000222855 | SCV000275564 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-05-04 | criteria provided, single submitter | clinical testing | The p.S2572* pathogenic mutation (also known as c.7715C>G) located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 7715. This changes the amino acid from a serine to a stop codon within coding exon 15. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). |
| Laboratory for Molecular Medicine, |
RCV000825577 | SCV000966911 | likely pathogenic | Familial multiple polyposis syndrome | 2018-04-17 | criteria provided, single submitter | clinical testing | The p.Ser2572X variant in APC has not been previously reported in individuals wi th familial adenomatous polyposis (FAP) or other APC-associated cancers and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 2572. This termination codon occurs within the la st exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss-of-function variants in the last exon of APC have bee n reported as disease causing in individuals with FAP. In summary, although addi tional studies are required to fully establish its clinical significance, the p. Ser2572X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2. |
| Invitae | RCV003743658 | SCV003263040 | pathogenic | Familial adenomatous polyposis 1 | 2023-07-19 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ser2572*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 272 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). 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: 231654). This variant has not been reported in the literature in individuals affected with APC-related conditions. |