Fig. 1: Characteristics of our cohort of c-CBL mutated patients.

A Flowchart of the study design and population selection. B Mutations distribution across the protein structure. Blue dots refer to missense mutations (MS), red dots to frameshift mutations (FS), yellow dots to truncating (T) (not in-frame indel, nonsense and splice-site) mutations. Underlined are the mutations further included in the analysis based on their pathogenicity. C Mutations selection. Mutations were divided according to their pathogenicity, functions (presumed from functional studies), and disease phenotype. We originally identified 322 mutations in 296 patients. Of these, the precise configuration was available in 261 cases (identified in 234 patients). According to our flow-chart, we selected, among MS variants, only tier 1–2 mutations occurring in linker region/zinc finger domains, and among T/FS variants, tier 1–2 mutations or mutations not previously described or with undefined pathogenicity, for a total of 203 variants in 184 patients: 147 harboring MS, 42 T/FS; 5 harboring both the type of mutation. More specifically, we included in MS cohort, 160 tier 1–2 mutations occurring in linker region/zinc finger domains (6 co-occurring with T/FS mutations) and in 21 T/FS tier 1–2 variants (2 co-occurring with canonical mutations) and 22 mutations without pathogenicity prediction (3 co-occurring with MS mutations). AML acute myeloid leukemia, FS frameshift, T truncating. *For the purposes of the analysis and based on literature reports we assumed that T/FS mutations not previously reported would be categorized as tier 2. **Mutations were considered multihits in case of two somatic lesions, VAF > 50%, del(11q) and/or chromosome 11 uniparental disomy.