Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000485953 | SCV000571311 | pathogenic | not provided | 2016-08-09 | criteria provided, single submitter | clinical testing | This insertion of one nucleotide in APC is denoted c.4778_4779insT at the cDNA level and p.Lys1593AsnfsX39 (K1593NfsX39) at the protein level. The normal sequence, with the base that is inserted in braces, is CAAAAAA[T]GCCA. The insertion causes a frameshift which changes a Lysine to an Asparagine at codon 1593, and creates a premature stop codon at position 39 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. |
| Invitae | RCV003743746 | SCV002119041 | pathogenic | Familial adenomatous polyposis 1 | 2023-10-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Lys1593Asnfs*39) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1251 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 421962). 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. 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. |
| Ambry Genetics | RCV003338608 | SCV004059070 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-08-11 | criteria provided, single submitter | clinical testing | The c.4778_4779insT pathogenic mutation, located in coding exon 15 of the APC gene, results from an insertion of one nucleotide at position 4778, causing a translational frameshift with a predicted alternate stop codon (p.K1593Nfs*39). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 1252 amino acids of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |