A substantial proportion of patients with adenomatous polyposis have no germline pathogenic variant in APC. The aim of this study was to determine the prevalence of APC mosaicism in these patients with unexplained polyposis and to draft guidelines for APC mosaicism testing and surveillance.

APC mosaicism was analyzed by targeted next-generation sequencing in 541 patients with a broad spectrum of polyposis phenotypes.

The rate of APC mosaicism was 9.4%. This rate was 14.3% (46 of 322) in patients who met the scope of national hereditary polyposis testing guidelines (≥10 adenomas before the age of 60 or with ≥20 adenomas before the age of 70). In patients who did not meet the scope of national guidelines, the detection rate was 2.3% (5 of 219). In patients with ≥20 adenomas before the age of 60 or ≥30 adenomas before the age of 70, the detection rate was ≥10%. Of 34 mosaic patients who underwent an esophagogastroduodenoscopy, 26% were diagnosed with gastroduodenal polyps. In 1 of the 2 patients tested, the mosaic variant was detected in semen, but none of the children tested in this cohort inherited the mosaic variant.

We recommend APC mosaicism testing at least in patients negative for germline pathogenic variants with (1) ≥20 adenomas before the age of 60 or (2) ≥30 adenomas before the age of 70. Regular colonoscopy and at least 1 gastroduodenoscopy should be offered to APC mosaic patients, with frequency of follow-up based on findings. Offering germline testing for offspring should be considered.