Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002341178 | SCV002618774 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-05-12 | criteria provided, single submitter | clinical testing | The c.3467_3470delAAGA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 3467 to 3470, causing a translational frameshift with a predicted alternate stop codon (p.E1156Gfs*8). This mutation has been reported in multiple patients with familial adenomatous polyposis (FAP) (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A., 1992 May;89:4452-6; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Gómez-Fernández N et al. BMC Med. Genet., 2009 Jun;10:57). 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. |
| Myriad Genetics, |
RCV003337297 | SCV004045484 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-08 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Department of Pathology and Laboratory Medicine, |
RCV000501415 | SCV000591143 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The p.Glu1156GlyfsX8 variant variant was identified in 6 of 2654 proband chromosomes (frequency: 0.002) from German, Spanish, American and Japanese individuals or families with FAP or AFAP (Gomez-Fernandez 2009, Miyoshi 1992, Friedl 2005); however, control chromosomes were not evaluated in these studies. In a series of 30 gastric adenomas screened for APC mutations, one was found to carry the variant, supporting a role for this APC gene mutation in early stages of gastric adenoma development (Tamura 1994). The variant was identified in, HGMD, COSMIC, InSiGHT Colon Cancer Gene Variant Database, and UMD (2X as unvalidated). In UMD the variant was identified with a co-occurring APC unclassified variant (c.2567delG). The p.Glu1156GlyfsX8 variant leads to a premature stop codon at position 1163, which is predicted to lead to 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.Notably, this variant occurs 50 base pairs before the penultimate exon junction in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |