Genome sequencing (sequencing of nearly all DNA) and exome sequencing (sequencing of protein-coding DNA) allow broad assessment of a wide range of genetic variants for diagnostic purposes in conditions including epilepsy, autism, and intellectual disability.1 Increasingly, genome and exome sequencing are being used in clinical settings when a genetic basis for disease is suspected, but the evaluation has not provided enough specificity to guide selection of a single gene test or a gene panel test. Sequencing is not currently indicated for healthy individuals for genetic risk screening,2 but it is used for opportunistic screening through evaluation of secondary (ie, incidental) findings.3 Clinicians must understand how to interpret findings from sequencing in the context of multiple sources of information in order to make the best decisions regarding patient care.