This study addresses a genetic mutation linked to Li-Fraumeni syndrome (LFS), a condition that heightens the risk of multiple early cancers. The mutation, located in the TP53 gene, disrupts its normal function. Initially considered uncertain, this novel variant was later redefined as “pathogenic” after demonstrating reduced activity of the p53 protein, which protects cells from cancer. We also discovered a novel part of the TP53 gene and a novel gene product. This study provides a genetic counseling for affected families, highlights the complexity of gene splicing in cancer, and contribute to advancing our understanding of p53 biology and LFS. (By Dr Gaëlle Bougeard-Denoyelle, https://jmg.bmj.com/content/early/2025/01/09/jmg-2024-110449 )