Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159589 | SCV000209570 | pathogenic | not provided | 2014-04-07 | criteria provided, single submitter | clinical testing | This duplication of 2 nucleotides is denoted APC c.3473_3474insGA (aka c.3473_3473dupGA) at the cDNA level and p.Pro1159AspfsX7 (P1159DfsX7) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GAGA{GA}CCAA. The duplication causes a frameshift, which changes a Proline to an Aspartic Acid at codon 1159 in exon 16, and creates a premature stop codon at position 7 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this variant has not been previously reported to our knowledge, it is considered pathogenic and is indicative of a Familial Adenomatous Polyposis (FAP)-associated condition, and could manifest as either classic FAP and attenuated FAP (AFAP), both autosomal dominant conditions characterized by the development of many polyps as well as colorectal and other cancers. Individuals with classic FAP may develop hundreds to thousands of adenomatous polyps by age 35 and are diagnosed with colon cancer by the average age of 39. The age-related risk for colon cancer in untreated individuals is 7% by age 21, 87% by age 45, and 93% by age 50 (Jasperson 2010). Individuals with AFAP develop an average of about 30 polyps and are typically diagnosed with colon cancer between ages 50 and 55. Attenuated FAP is distinguished from classic FAP primarily by the difference in polyp burden and age at presentation. Although some regions of the APC gene are more strongly associated with AFAP than others, clinical presentation is the most appropriate way to determine a family's genetic condition at this point. Both FAP and AFAP have extra-colonic features, though the risks are much lower than for colon polyps and cancer. Both conditions confer a 5% risk for duodenal or periampullary cancer, and a 1-2% risk for stomach, thyroid, pancreatic cancer, medulloblastoma and hepatoblastoma, with the latter two seen predominantly in FAP, not AFAP (Jasperson 2012). About 10-30% of individuals with FAP display desmoids tumors. Upper gastrointestinal tract polyps and fundic gland polyps are present in most cases of classic FAP and AFAP. Gardner syndrome is a variant of FAP in which colonic polyposis are observed along with osteomas, epidermoid cysts, fibromas, and/or desmoid tumors. Approximately 20-25% of APC mutations are de novo, rather than inherited. |