Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| MGZ Medical Genetics Center | RCV002289950 | SCV002580141 | likely pathogenic | Familial adenomatous polyposis 1 | 2021-09-07 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002331296 | SCV002627162 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-09-21 | criteria provided, single submitter | clinical testing | The c.4127_4128delAT pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 4127 to 4128, causing a translational frameshift with a predicted alternate stop codon (p.Y1376Cfs*9). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This pathogenic variant has been reported in several unrelated patients/families with a clinical diagnosis of FAP or AFAP (Friedl W et al. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Aceto G et al. Hum. Mutat. 2005 Oct;26:394; Lagarde A et al. J. Med. Genet. 2010 Oct;47:721-2; Chen QW et al. Asian Pac. J. Cancer Prev. 2015;16:4915-20). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV002289950 | SCV003439278 | pathogenic | Familial adenomatous polyposis 1 | 2022-01-01 | criteria provided, single submitter | clinical testing | 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: 548663). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis (FAP) (PMID: 20223039). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1376Cysfs*9) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1468 amino acid(s) of the APC protein. |
| Myriad Genetics, |
RCV000662306 | SCV004044779 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-10 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Yale Center for Mendelian Genomics, |
RCV000662306 | SCV000784637 | pathogenic | Familial adenomatous polyposis 1 | 2015-11-27 | no assertion criteria provided | literature only |