RB1 and retinoblastoma: On the other hand, the penetrance and expressivity of heritable retinoblastoma may be determined by the mutation type in RB1. Nonsense and frameshift mutations typically cause multifocal bilateral tumors due to the absence of the retinoblastoma protein, whereas intronic splice mutations are associated with incomplete penetrance and milder expressivity due to a residual function of the retinoblastoma polypeptide [7,18,24,34,35].