Measuring disease likelihood in genomic ascertainment

Understanding the yield, predictive power, and utility of a secondary finding is critical for policy development and can help inform discussions for population screening. Because American College of Medical Genetics and Genomics (ACMG) Secondary Findings guidelines are applied in diverse testing contexts, we recruited participants from multiple sources to address these questions. We assessed our first 1,500 inquiries to review the disorders/genes that were returned to these individuals. After eligibility screening, we enrolled 227 recipients and completed genotyping, cascade testing, and phenotyping efforts for 163 probands. From evaluating these families, it became clear that there were highly variable outcomes for the diagnostic yield of secondary findings. To objectively and quantitatively assess this, we developed a method to measure the likelihood that the family was, in fact, affected with the disorder associated with the secondary finding variant. We assessed this in detail for 59 families who had a secondary finding of BRCA1- or BRCA2-related cancer predisposition. Our estimates of the likelihood of a valid clinicomolecular diagnosis ranged from 26.2% to 100%. Over half (51%) of the families met criteria for diagnostic testing, indicating that diagnostic testing for these disorders is underused and that secondary findings testing is being applied inappropriately to these families. These results will be useful for policy refinement for secondary findings and are also relevant to considerations of population genomic screening.