Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000491310 | SCV000579842 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-01-22 | criteria provided, single submitter | clinical testing | The p.E1353* pathogenic mutation (also known as c.4057G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 4057. This changes the amino acid from a glutamic acid to a stop codon within coding exon 15. In a large (n=1591) series of patients referred for APC testing, this alteration was detected in 1 individual (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). In another study, this alteration was identified in 1/87 unrelated individuals with familial adenomatous polyposis (Papp J et al. Fam. Cancer, 2016 Jan;15:85-97). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV003335385 | SCV002240075 | pathogenic | Familial adenomatous polyposis 1 | 2021-04-23 | criteria provided, single submitter | clinical testing | 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 been observed in individual(s) with clinical features of familial Adenomatous Polyposis (PMID: 23159591, 26446593). ClinVar contains an entry for this variant (Variation ID: 428122). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu1353*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1491 amino acid(s) of the APC protein. |
Myriad Genetics, |
RCV003335385 | SCV004045580 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-10 | 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. |