BACKGROUND: Adenomatous polyposis confers an increased risk of developing colorectal cancer. and are the major genes investigated in patients suspected of having polyposis. In addition to and genes, other genes, such as , and , have recently been associated with polyposis phenotypes, conferring heterogeneity in terms of the clinical, etiological and heritable aspects of patients with polyposis. AIM: To investigate the underlying variant landscape in patients with suspected polyposis who lack variants in the and genes using whole-exome sequencing. METHODS: Twenty-seven participants were included in the study and subjected to germline whole-exome sequencing. In addition, their clinical-pathological, personal, and family history data were collected. RESULTS: The mean age at diagnosis was 51 years, and most participants had attenuated forms of polyposis (88.9%), with 63.0% diagnosed with a primary tumor, mostly colorectal cancer (76.5%). Among the variants identified, 17 were classified as pathogenic or likely pathogenic (in 12 participants), including variants in genes involved in the Wnt/β-catenin signaling pathway, such as , , and , and variants in DNA-repair genes, such as , and , as well as a variant found at the gene identified in a patient with classic polyposis at age 19 and with a family history of polyps. CONCLUSION: This study identified novel genes potentially associated with polyposis in patients lacking germline pathogenic variants in the and genes. These findings support the use of next-generation sequencing for screening, expanding the scope of polyposis-related variants beyond these two genes.