Abstract
Human genome sequencing is routine and will soon be a staple in research and clinical genetics. However, the promise of sequencing is often just that, with genome data routinely failing to reveal useful insights about disease in general or a person's health in particular. Nowhere is this chasm between promise and progress more evident than in the designation, "variant of uncertain significance" (VUS). Although it serves an important role, careful consideration of VUS reveals it to be a nebulous description of genomic information and its relationship to disease, symptomatic of our inability to make even crude quantitative assertions about the disease risks conferred by many genetic variants. In this perspective, I discuss the challenge of "variant interpretation" and the value of comparative and functional genomic information in meeting that challenge. Although already essential, genomic annotations will become even more important as our analytical focus widens beyond coding exons. Combined with more genotype and phenotype data, they will help facilitate more quantitative and insightful assessments of the contributions of genetic variants to disease.