Atypical clinical presentations of APC-associated polyposis linked to pathogenic variants c.1333C>T p.(Gln445Ter) and c.221-2A>G p.(?) – two case reports

Background Different germline pathogenic variants in the adenomatous polyposis coli ( APC ) gene can confer mild to severe presentations of familial adenomatous polyposis (FAP) with phenotypes ranging from attenuated FAP with multiple polyps to florid polyposis with high risk for colorectal cancer (CRC) development, often at a young age. FAP can be accompanied by extra-colonic manifestations, including desmoid and other tumors. We report two index cases with atypical clinical presentations and distinct disease trajectories associated with two rare germline pathogenic variants of APC . Case presentation: Patient 1 was an African American male who presented with increasingly high polyposis burden between the ages of 31 and 33 years and rectal cancer at 33 years. He also had a history of cranial fasciitis in infancy and dermal cysts. Germline genetic testing revealed the APC c.1333C > T p.(Gln445Ter) nonsense variant. He had no family history of polyposis or CRC but did have a family history of cranial fasciitis. His family declined cascade genetic testing. Exome sequencing revealed additional germline heterozygous pathogenic variants in NBAS and RXYLT1 that were considered unlikely to have contributed to his phenotype. Multiple somatic mutations in APC and other CRC-associated driver genes were identified in the rectal tumor, consistent with polyclonal origins in carcinogenesis. Patient 2 is a European female with a family history of serial and multiple polyps who developed multiple polyps over a decade of follow-up. Germline genetic testing revealed the APC c.221-2A > G splice variant in her and first-degree relatives. RNA analyses in her normal tissues and polyps revealed distinct aberrantly spliced transcripts, which were outnumbered by normal transcripts in normal tissues, providing one possible explanation for her milder phenotype, and enriched in polyps. Conclusions These case reports illustrate the spectrum and complexity of genotype-phenotype correlations observed among APC pathogenic variants and the importance of comprehensively integrating clinical, family history, genetic, and functional information when evaluating individualized risk and surveillance strategies.