Changes in the approach to the analysis and evaluation of inherited pathogenic TP53 variants

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disorder characterized by an extreme lifetime risk of multiple and early-onset tumors, driven by inherited pathogenic variants in the TP53 gene. While somatic mutations in TP53 are among the most frequent genetic alterations in cancer, germline mutations remain rare. Although LFS has long been recognized as a prototypical cancer predisposition syndrome, recent advances have significantly reshaped its diagnostic criteria and deepened our understanding of its associated cancer risks.

The review illustrates the evolving diagnostic landscape of LFS and the updated indication criteria for germline TP53 testing, which have broadened the definition of the syndrome into the more inclusive entity of heritable TP53-related cancer predisposition syndrome (hTP53rc). The adoption of NGS has streamlined molecular diagnostics in hereditary cancer syndromes. Germline analysis of TP53 has become standard practice in hereditary cancer predisposition testing, even if a proband does not exhibit a LFS phenotype. However, the accurate identification of germline pathogenic TP53 variants remains challenging, particularly due to confounding factors, such as mosaicism or clonal hematopoiesis of indeterminate potential. Confirmatory testing using an independent tissue sample, along with estimation of allelic fraction is necessary to distinguish true germline variants. Another major hurdle is the assessment of the pathogenicity of rare germline TP53 variants, which requires a thorough genotype-phenotype correlation analyses. Recently, gene-specific American College of Medical Genetics and Genomics / Association for Molecular Pathology criteria have been introduced to support the classification of germline TP53 variants. Importantly, only carriers of a clearly established germline pathogenic variant should be considered for inclusion in an intensive clinical surveillance and prevention program.

The present work underscores a paradigm shift in the understanding of one of the most significant cancer predisposition syndromes and aims to stimulate further discussion on the organization of care for high-risk carriers of pathogenic TP53 variants in the Czech Republic.