The adenomatous polyposis coli (APC) protein is a negative regulator of the mitogenic transcription factor beta-catenin by stimulating its proteasomal degradation. This involves several APC domains, including the binding sites for axin/conductin, the recently described beta-Catenin Inhibitory Domain (CID) and the third 20 amino acid repeat (20R3) that is a beta-catenin-binding site. The four 15 amino acid repeats (15R) and the 20R1 are also beta-catenin-binding sites, but their role in beta-catenin degradation has remained unclear. We show here that binding of beta-catenin to the 15R of APC is necessary and sufficient to target beta-catenin for degradation whereas binding to the 20R1 is neither necessary nor sufficient. The first 15R displays the highest affinity for beta-catenin in the 15R-20R1 module. Biallelic mutations of the APC gene lead tocolon cancer in familial adenomatous polyposis coli (FAP) and result in the synthesis of truncated products lacking domains involved in beta-catenin degradation but still having a minimal length. The analysis of the distribution of truncating mutations along the APC sequence in colorectal tumours from FAP patients revealed that the first 15R is one target of the positive selection of mutations that lead to tumour development.