The APC gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. APC promotes rapid degradation of beta-catenin and participates in Wnt signaling as a negative regulator. APC is also involved in other processes including cell migration, cell adhesion, transcriptional activation and apoptosis. Germline defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. There is a case report of renal cell carcinoma occurring in a patient with attenuated FAP and a heterozygous germline APC deletion. Somatic APC mutations have been reported in ~1% of clear cell renal cell carcinomas. Codon I1307 lies within a regulatory region of the APC protein mediated by ubiquitination. APC I1307K is associated with increased colorectal cancer risk by making the gene unstable and prone to acquire mutations during normal cell division. The germline APC I1307K gene mutation is most commonly found in people of Ashkenazi Jewish descent. Therefore, routine colorectal screening is very important in these individuals. The prognostic and therapeutic implications of APC mutations in renal cell carcinoma remain to be fully elucidated. Correlation with other clinical and lab findings is recommended.