A novel insertion/deletion in APC promotor 1B is associated with both gastric and colon polyposis.

Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.