As compared to all other cancer types, our analysis highlights the highly specific landscape of TP53 alterations in CLL, one comprising three distinct features: (i) a high prevalence of TP53-mutated minor clones (VAF below 5%), (ii) an important intratumoral heterogeneity with multiple subclones expressing different TP53 variants, and (iii) multiple CLL-specific mutation hotspots. Here, TP53 is linked to B-cell chronic lymphocytic leukemia.