Background <p>Hypopharyngeal squamous cell carcinoma is a rare and aggressive malignancy of the upper aerodigestive tract. While tobacco and alcohol remain the primary etiologic factors, hereditary cancer predisposition syndromes—particularly those involving germline TP53 mutations—can contribute to early onset disease.</p> Case presentation <p>We report a case of a 45-year-old Iranian male patient with moderately differentiated hypopharyngeal squamous cell carcinoma, significant family history of upper aerodigestive and breast cancers, and identification of a germline TP53 variant of uncertain significance (c.743G &gt; A;p.Arg248Gln). The patient’s family history included a mother with breast cancer diagnosed at age 42&#xa0;years, a brother with laryngeal cancer diagnosed at age 38&#xa0;years, and a maternal aunt with esophageal cancer diagnosed at age 50&#xa0;years. The patient underwent induction chemotherapy, concurrent chemoradiotherapy, and surgical resection, achieving complete remission. The clinical context and family history met Chompret criteria for Li-Fraumeni-like syndrome, prompting genetic counseling and family-based surveillance.</p> Conclusion <p>This case highlights the importance of germline genetic evaluation in early onset head and neck cancers with familial clustering. Variants of uncertain significance in TP53 pose clinical challenges and require long-term surveillance, multidisciplinary care, and patient-centered counseling.</p>