Elena BULANCEA, Stefania IORDACHE, Cerasela JARDAN, Onda-Tabita CALUGARU
Introduction: Variants of uncertain significance (VUS) in cancer predisposition genes, such as TP53, represent a major challenge in clinical interpretation. The p53 protein functions as a tumor suppressor involved in cell cycle regulation, apoptosis, and DNA repair mechanisms. Loss-of-function variants may contribute to the development of various cancer types or to the Li-Fraumeni syndrome. The DNA-binding domain (DBD) is essential for p53 function, and variants occurring within this region may have significant functional impact.
Materials and Methods: TP53 variants located within the DNA-binding domain and classified as VUS were extracted from the ClinVar database. A total of 93 variants met the inclusion criteria and were re-evaluated according to ACMG/AMP guidelines and available literature data. Bioinformatic tools, including gnomAD and MutationTaster, were used to support the reclassification process.
Results: Among the 93 VUS variants analysed, 6 variants (6.45%) retained their VUS status, whereas 87 variants (93.55%) were reclassified as Likely Pathogenic, supporting the clinical relevance of their localization within a key functional domain. Although six variants initially reached a cumulative score of 5 points, partly due to their absence from large population databases such as gnomAD, the available evidence was insufficient to justify a change toward a benign classification.
Conclusions: Reclassification of TP53 variants within the DNA-binding domain highlights the importance of periodic re-evaluation of VUS. The integration of functional, bioinformatic, and clinical data, together with expert genetic assessment, is essential for accurate diagnostic interpretation and appropriate clinical management.
Keywords: TP53 variants, Variants of uncertain significance (VUS), ACMG/AMP guidelines
https://doi.org/10.59854/dhrrh.2026.4.2.43
Cite this article
Bulancea E., Iordache S., Jardan C., Calugaru O.-T., ACMG-Based Reclassification of TP53 Variants in Oncogenetic Practice. DHRRH, 2026, 6(2), https://doi.org/10.59854/dhrrh.2026.4.2.43
