We report a new class of molecular lesions in the 5' region of the BCL2 protooncogene when it undergoes a t(14;18) translocation-associated rearrangement in the major break cluster (MBR) or minor break cluster (MCR) regions. Among 52 tumors assayed for BCL2 rearrangements using the MBR, MCR, and 5' probes, seven (six with MBR and one with MCR translocation breaks) showed aberrant bands in unique enzyme digests of DNA hybridized with the 5' probe. The aberrant bands in four tumors were in HindIII digests, in two they were in EcoRI digests, while the aberrant band in one was in a BamHI digest. The two EcoRI bands and two of the four HindIII bands were of identical sizes. Germline polymorphisms as the source of these bands was ruled out by appropriate control experiments. These results suggest that the bands were derived from point mutations or small deletions in the 5' region of BCL2. The significance of this alteration to BCL2 function in translocation-carrying tumors remains to be determined.