Most genetic predisposition to cancer relates to sequence variation, but there are other genetic mechanisms which may influence cancer risk, such as methylation defects (constitutional MLH1 hypermethylation [3]), imprinting disorders (e.g., Beckwith–Wiedemann syndrome [4]), and copy-neutral structural rearrangements [5] (e.g., MSH2 inversion [6] and chromosome 3 translocations involving VHL [7]), which are not readily detected by whole genome sequencing. The gene discussed is MSH2; the disease is cancer.