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BACKGROUND: Advances in genomics have led to calls for returning information about medically actionable genes (MAGs) to patients, research subjects, biobank participants, and through screening programs, the general adult population. Which MAGs are returned affects the harms and benefits of every genetic testing endeavor. Despite published recommendations of selection criteria for MAGs to return, scant data exist regarding how decision makers actually apply such criteria. METHODS: The process and criteria used by researchers when selecting MAGs for a preventive genomic sequencing program targeting the general adult population were examined. The authors observed and audio-recorded the gene selection meetings, and analyzed meeting transcripts, gene scoring sheets, and meeting handouts. RESULTS: To select MAGs, the committee imported, from a preexisting project, “a semiquantitative metric” that scores genes on five criteria. Numerous subjective judgments and conceptual challenges in defining and applying the five criteria complicated the selection process. Criteria-related challenges also included the limited evidence available about facts fundamental to the scoring decisions and the emergence and application of criteria that were not part of the original metric. CONCLUSIONS: When identifying MAGs appropriate for screening and return, decision makers must expect and prepare to address such issues as the inevitability of subjective judgments, limited evidence about fundamental decision-making elements, the conceptual complexity of defining criteria, and the emergence of unplanned criteria during the gene selection process.