DNA rearrangements resulting in human genome structural variants (SVs) are caused by diverse mutational mechanisms. We used long- and short-read sequencing technologies to investigate end products of de novo chromosome 17p11.2 rearrangements and query the molecular mechanisms underlying both recurrent and non-recurrent events. Evidence for an increased rate of clustered single-nucleotide variant (SNV) mutation in cis with non-recurrent rearrangements was found. Indel and SNV formation are associated with both copy-number gains and losses of 17p11.2, occur up to ∼1 Mb away from the breakpoint junctions, and favor C > G transversion substitutions; results suggest that single-stranded DNA is formed during the genesis of the SV and provide compelling support for a microhomology-mediated break-induced replication (MMBIR) mechanism for SV formation. Our data show an additional mutational burden of MMBIR consisting of hypermutation confined to the locus and manifesting as SNVs and indels predominantly within genes. Display omitted •Orthogonal DNA sequencing approaches are required to observe all variant types•De novo SNVs and indels accompany non-recurrent structural variants (SVs) in cis•SV-associated SNVs primarily occur within genes and over megabase-sized distances•MMBIR involves extensive DNA replication resulting in regional hypermutation Newly occurring structural variants within human genomes spawn extensive, local single-nucleotide changes leading to an enhanced mutational burden within proximal genes.