This case underscores the diagnostic and management complexities introduced by germline TP53 VUS, particularly in patients meeting Li-Fraumeni-like syndrome (LFL) criteria. The p.Arg248Gln variant lies in a mutational hotspot and may impair DNA binding and transcriptional regulation, though functional validation remains incomplete. The p.Arg248 residue is critical for TP53’s DNA-binding function, and mutations at this site have been associated with altered protein stability and transcriptional activity in prior studies [5, 6]. However, the lack of functional assays or family segregation studies for this specific variant limits its classification as pathogenic.
According to ClinVar (accessed October 2024), the TP53 c.743G > A (p.Arg248Gln) variant has conflicting interpretations of pathogenicity. Some submissions classify it as “likely pathogenic,” while others consider it a “variant of uncertain significance.” In silico tools such as PolyPhen-2, SIFT, and REVEL predict this variant to be damaging to protein function. The patient’s early disease onset and strong family history of cancers (breast, laryngeal, esophageal) meet the Chompret criteria for LFL, supporting a high-suspicion approach to management despite the VUS classification. The Chompret criteria emphasize early onset cancers and specific tumor types, including breast, head and neck, and esophageal cancers, as seen in this patient’s family [5]. Surveillance guidelines, such as the Toronto protocol, recommend annual whole-body MRI and targeted cancer screening for individuals with LFL or LFS [7].
The absence of p16 and p53 IHC data limit the ability to assess HPV status or confirm the functional impact of the TP53 variant on the tumor. Future studies should prioritize these tests to enhance diagnostic precision. Management of patients with TP53 VUS requires a multidisciplinary approach, integrating oncology, clinical genetics, and psychological support. Regular reassessment of VUS classification is essential as new functional or segregation data emerge.