Mapping of variants in TCR signaling genes mutated in at least 3 patients. (A) CD28: the D124V/E variants involve the extracellular part of the receptor, whereas T195P lies in the intracellular, C-terminal, domain between the 2 domains, allowing interaction with PIK3R1 (YVKM sequence) or GRB2/VAV (PRRP sequence) proteins. (B) FYN: the five mutations indicated occurred in three patients; 1 patient harbored 2 mutations (a); 2 mutations in adjacent positions in the SH3 domain (b) were observed on the same allele in another patient. (C-E) PI3K subunits: when appropriate, cellular stimuli are present, the nSH2 and cSH2 domains of PIK3R1 bind phosphorylated tyrosines (YXXM motif) in activated receptors (CD28) and adapter proteins, thereby activating the PIK3CA (p110a) catalytic subunit without releasing the PIK3R1 (p85a) interaction with p110a through their iSH2 and ABD domains, respectively. The K141R missense affects the ρ-GAP domain, whereas iSH2 and the second SH2 domains of PIK3R1 bore 2 missenses each (Q475P, T576A and G680S, V704M, respectively). The A259V mutation, described as somatic in COSMIC, affects a linker region of PIK3R5. Finally, the L1001P point mutation affects the PIK3CA kinase domain. (F) PDK1: one inframe INDEL, one frameshift INDEL, and 3 missense affect PDK1 protein. (G) CTNNB1: 3 previously described activating missenses affect the GSK3β inhibitory domain (exon 3), whereas the K335T activating mutation affects the armadillo repeats region. (H) KRAS: 3 missense mutations alter 2 N-terminal nucleotide binding regions. (I) GTF2I: 5 missense mutations affect the GTF2I transcription factor, among which two are found in different GTF2I-like domains. (J) VAV1: 2 frameshift deletions and 2 missenses affect VAV1, three being localized in the C-terminal SH3 domain of the protein. In all figure panels, previously described activating mutations are in green boldface, and mutations previously described but not functionally tested are underlined. PDK1 is the protein name of PDPK1 gene.