Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Department of Pathology and Laboratory Medicine, |
RCV000500692 | SCV000591025 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The APC p.Gly116LysfsX18 variant was not identified in the literature nor was it identified in the in dbSNP, Clinvitae database, COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, UMD, NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium database (August 8, 2016) databases. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The c.346_359del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 116 and leads to a premature stop codon 18 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. This alteration would typically be predicted to result in a truncated or absent protein and loss of function; however, one study has demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |