AbstractThe antigen receptor loci are the only loci in humans to undergo programmed somatic gene modification. Although aberrant V(D)J integration and class switch recombination can both give rise to chromosomal translocations, a role for somatic hypermutation in such genomic rearrangements has been suggested but is less clearly established. To characterize the types of by‐products of somatic hypermutation, we analyzed aberrant rearrangements involving the immunoglobulin loci in a human B‐cell line (Ramos) that performs Ig V gene hypermutation constitutively during culture. Single‐nucleotide substitutions account for 95% of the mutational events in the VH gene, with small deletions and duplications accounting for most of the remaining mutations. However, larger genetic alterations can be detected at low frequency, accounting for 0.5% of VH‐inactivating mutations. Examples include a large (13 kb) deletion, which entirely removes the expressed VH gene; a 3‐kb deletion extending from the functional VHDJH into an upstream VH (generating a hybrid VHDJH gene reminiscent of VH replacement); and an ectopic insertion into the VH from chromosome 1. The results support the proposal that aberrant antibody hypermutation can lead to gross genomic alterations but indicate that such events are rare. © 2003 Wiley‐Liss, Inc.