These were the most common causal mutation, R649W, which abolishes phosphotyrosine binding by the C-terminal SH2 (cSH2) domain (Chudasama et al., 2013), Y657X, which truncates the cSH2 domain (Huang-Doran et al., 2016; Kwok et al., 2020), and E489K which, atypically, lies in the inter-SH2 domain where most cancer, overgrowth, and APDS2-associated mutations lie (Thauvin-Robinet et al., 2013). The gene discussed is CSH2; the disease is cancer.