Mosaic TP53 pathogenic variant in early-onset breast cancer: a case report

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer predisposition syndrome caused by pathogenic variants in the TP53 gene. The increasing use of next-generation sequencing (NGS) in germline testing has led to more frequent detection of TP53 variants with low variant allele frequency (VAF), raising diagnostic challenges in distinguishing true germline alterations from post-zygotic mosaicism or clonal hematopoiesis and circulating tumor DNA, with relevant clinical and counseling implications. We report a 30-year-old woman diagnosed with early-onset HER2-positive breast cancer who underwent genetic counseling for suspected hereditary cancer predisposition. Germline NGS identified a pathogenic TP53 variant with low VAF (16.7%) in peripheral blood, suggestive of a non-germline event. To clarify its origin, additional molecular analyses were performed on non-hematopoietic tissues. The same variant was detected in buccal cells (ectoderm) and skin fibroblasts (mesoderm), and subsequently confirmed in normal colonic mucosa (endoderm), demonstrating the presence of the pathogenic variant across all three embryonic germ layers. These findings support an early post-zygotic origin and confirm generalized post-zygotic mosaicism. Based on this molecular characterization, a personalized surveillance and management strategy was implemented. This case provides rare and robust molecular evidence of TP53 post-zygotic mosaicism involving all three embryonic germ layers in a patient with early-onset breast cancer. It highlights the importance of extended tissue testing to correctly interpret low-VAF TP53 variants and to distinguish mosaicism from clonal hematopoiesis and circulating tumor DNA. Recognition of TP53 mosaicism has significant implications for cancer risk assessment, surveillance strategies, and genetic counseling, underscoring the need for individualized clinical management in the absence of specific guidelines.

This case report highlights the increasing diagnostic challenges posed by low-VAF TP53 variants detected through germline NGS and emphasizes the critical importance of extended tissue testing to distinguish true germline variants from post-zygotic mosaicism and clonal hematopoiesis or circulating tumor DNA. Our findings have direct clinical implications for cancer risk assessment, surveillance strategies, and genetic counseling, particularly in young patients with early-onset tumors belonging to the Li-Fraumeni syndrome spectrum. To our knowledge, this represents a rare and well-documented example of TP53 post-zygotic mosaicism involving all three embryonic germ layers, supported by comprehensive molecular characterization. We believe that this report provides valuable insights for clinicians, geneticists, and oncologists involved in hereditary cancer risk assessment and management.