Cytoplasmic actins are abundant molecules in non-muscle cells, including white blood cells. Two forms exist which are referred to as beta- or gamma-cytoplasmic actin encoded by

ACTB

and

ACTG1

, respectively. They form the building blocks of the dynamic actin polymers of the cytoskeleton that are involved in migration and motility processes of cells. Whereas mutations in cytoplasmic actins have been discovered in congenital diseases, their prevalence in cancer types has not been studied in detail. We show that within hematological cancer cytoplasmic actin mutations occur with higher frequency in two specific subtypes. Beta-actin mutations occur mainly in the subtype diffuse large B-cell lymphoma or DLBCL whereas gamma-actin mutations occur mainly in multiple myeloma. Mapping these mutations on the three dimensional structure reveals they map to regions of actin that are important in actin polymer formation and, for gamma-actin also for myosin interaction. Given their occurrence in these functionally important regions, their role as potential driver mutations or in disease progression merits further investigation.