Background Gardner syndrome (GS) is an autosomal dominant disorder caused by mutations in the adenomatous polyposis coli (APC) gene, a tumor suppressor, located on chromosome 5q21 that consists of 15 exons encoding 2843 amino acids. The adenomatous polyposis coli (APC) protein plays a role in cell growth regulation by ensuring appropriate timing in the cell cycle. The clinical presentation of Gardner syndrome involves mainly gastrointestinal polyps, soft tissue tumors, and multiple osteomas. Dental manifestations include retained deciduous teeth, impacted teeth, hypercementosis, odontomas, dentigerous cysts, supernumerary teeth, and fused or long roots. Objectives This study aims to investigate the clinical, oro-dental, and genetic analysis of Gardner syndrome in two unrelated families from Egypt. Patients and methods This study included five Gardner syndrome patients from two unrelated families from Egypt. Whole exome sequencing (WES) was performed to investigate the genetic aetiology in two patients, one from each family. Mutation analysis of the identified APC gene variants will be extended to the siblings and their mothers. This analysis will be performed using PCR amplification followed by Sanger sequencing of the amplified fragments. Results Clinical examination revealed varied dental anomalies among patients. Specifically, one patient presented with mandibular osteomas. Supernumerary teeth were observed in three patients, while another patient exhibited retained deciduous teeth and multiple impacted teeth. Whole-exome sequencing identified two previously reported variants in the APC gene. A pathogenic (NM_000038.6):c.4666dupA variant was identified in a male patient from family 1. Additionally, a benign intronic (NM_000038.6):c.423-4delA variant was detected in a female patient from family 2. Segregation analysis confirmed the presence of both variants in a heterozygous state within affected siblings and their mothers in both respective families. Conclusion This study represents the first molecular analysis of the APC gene in Gardner syndrome patients in Egypt. The findings expand the spectrum of reported variants associated with Gardner syndrome, though further functional studies are required to confirm the deleterious nature of the identified variants.