Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003538421 | SCV000768036 | pathogenic | Familial adenomatous polyposis 1 | 2017-09-20 | criteria provided, single submitter | clinical testing | Different variants (c.3786T>A and c.3785dupA) giving rise to the same protein effect observed here (p.Tyr1262*) have been reported as pathogenic in individuals affected with familial adenomatous polyposis (PMID: 11247896, Invitae). In addition, a different truncation downstream of this variant (p.Ser1276*) has been determined to be pathogenic (PMID: 9452101, 10094547, 15108286, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. While this variant has not been reported in the literature in APC-related diseases, loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the APC gene (p.Tyr1262*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 1582 amino acids of the APC protein. |
| Ambry Genetics | RCV001021134 | SCV001182711 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-06-21 | criteria provided, single submitter | clinical testing | The p.Y1262* pathogenic mutation (also known as c.3786T>G), located in coding exon 15 of the APC gene, results from a T to G substitution at nucleotide position 3786. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. This alteration is expected to result in loss of function by premature protein truncation. A different nucleotide change that lead to the same amino acid impact, c.3786T>A, has been reported in individuals with familial adenomatous polyposis (Friedl W et al. Gut. 2001 Apr;48:515-21; Stekrova J et al. BMC Med. Genet. 2007 Apr;8:16). As such, this alteration is interpreted as a disease-causing mutation. |
| ARUP Laboratories, |
RCV001811417 | SCV002049021 | pathogenic | not provided | 2021-05-08 | criteria provided, single submitter | clinical testing | The APC c.3786T>G; p.Tyr1262Ter variant (rs147411334), to our knowledge, is not reported in the medical literature but is reported as pathogenic in ClinVar (Variation ID: 537417). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the APC gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein lacking 1582 amino acids. Another nonsense variant at the same codon (c.3786T>A; p.Tyr1262Ter) has been reported in patients affected with familial adenomatous polyposis and is considered disease-causing (Friedl 2001, Stekrova 2007). Based on available information, the c.3786T>G; p.Tyr1262Ter variant is considered to be pathogenic. References: Friedl W et al. Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families. Gut. 2001 Apr;48(4):515-21. PMID: 11247896. Stekrova J et al. Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects. BMC Med Genet. 2007 Apr 5;8:16. PMID: 17411426. |
| Myriad Genetics, |
RCV002533274 | SCV004044875 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-09 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |