Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000493028 | SCV000581426 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-03-25 | criteria provided, single submitter | clinical testing | The c.4319delC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at position 4319, causing a translational frameshift with a predicted alternate stop codon (p.P1440Hfs*33). This alteration has been identified in a juvenile FAP patient (Gutierrez Sanchez LH et al. Gastrointest Endosc. 2018 Mar;87(3):648-656). 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. |
| Gene |
RCV000657482 | SCV000779217 | pathogenic | not provided | 2018-03-08 | criteria provided, single submitter | clinical testing | This deletion of one nucleotide in APC is denoted c.4319delC at the cDNA level and p.Pro1440HisfsX33 (P1440HfsX33) at the protein level. The normal sequence, with the base that is deleted in brackets, is CCTC[delC]ACCA. The deletion causes a frameshift which changes a Proline to a Histidine at codon 1440, and creates a premature stop codon at position 33 of the new reading frame. This variant is predicted to cause loss of normal protein function through protein truncation. APC Pro1440HisfsX33 has been reported as a somatic variant identified in an adenoma from an individual with Familial Adenomatous Polyposis (Yamaguchi 2014). We consider this variant to be pathogenic. |
| Invitae | RCV003743759 | SCV003239922 | pathogenic | Familial adenomatous polyposis 1 | 2022-09-29 | criteria provided, single submitter | clinical testing | 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 429058). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1440Hisfs*33) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1404 amino acid(s) of the APC protein. |