Residue 376 has been designated as a cancer hotspot, with the variant itself, p.(Gly376Arg), functionally characterized as capable of inducing in vitro oncogenic transformation and activation of p110α.19,20 In total, the observed clinical features among the individuals assembled within our cohort suggest that somatic mosaic variants in PIK3R1 activate the PI3K pathway; however, the degree of activation, particularly in comparison to disease-associated variation in PIK3CA, requires further study. This evidence concerns the gene PIK3R1 and cancer.