In 4 families (2, 4, 5, and 6) with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS; 619182), 1 of which was the US family originally described by Worthley et al. (2012) as family 2, Li et al. (2016) identified heterozygosity for a c.-191T-C transition (c.-191T-C, NM_001127511) in a YY1 binding motif of the APC promoter 1B that segregated with disease in all 4 families and was not found in 344 germline samples from an in-house WGS cancer project or in the 1000 Genomes Project database. By EMSA, Li et al. (2016) demonstrated that the c.-191T-C mutation disrupts binding to the promoter 1B region in both AGS and RKO cells. In luciferase reporter assays, constructs with c.-191T-C showed significantly decreased activity compared to wildtype.
In a father and 3 daughters from a 3-generation Czech family with GAPPS, Repak et al. (2016) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA analysis was not reported for the paternal grandmother who also had proximal gastric polyposis and died of gastric cancer at age 49 years.
In a 38-year-old Austrian woman with GAPPS, Beer et al. (2017) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. DNA was unavailable from her father, who died of gastric cancer at age 57 years.
In 24 individuals from 8 Czech families with GAPPS, Foretova et al. (2019) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B. Of the 24 mutation carriers, 20 had massive gastric polyposis; in addition, 1 female carrier had incipient polyposis at age 58 years, 2 female carriers did not have polyposis of the stomach at ages 31 and 65, and a 92-year-old asymptomatic male carrier did not undergo gastroscopy due to his advanced age.
In affected members of 2 multiplex Japanese families with GAPPS, Kanemitsu et al. (2021) identified heterozygosity for the c.-191T-C variant in the APC promoter 1B.