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). This evidence concerns the gene CSH2 and cancer.