The implementation of genome and exome sequencing creates challenges and opportunities. We propose to pilot the implementation of exome sequencing for incidental/secondary findings in the NIHCC and measure its perceived utility. Through the Clinical Center Genomics Opportunity (CCGO), we have offered to investigators in 10 institutes access to exome sequencing for gene identification studies of their rare disease patients. We are using this research resource to increase the research use of genomics outside NHGRI, to begin to build the NIHCC clinical laboratory infrastructure to support genome scale data, and to familiarize clinicians in the NIHCC with genomic medicine. To accomplish these clinical goals, we propose to generate exome data in a CLIA- (NotEqual)compliant environment at NISC and use those data to evaluate patients for the presence of variants in genes recommended by the American College of Medical Genetics and Genomics policy on incidental and secondary findings, which is consistent with the policy recommendations of the Presidential Commission for the Study of Bioethical Issues. Thus, the exome data will have a dual purpose the entire dataset will be available for research to the ordering principal investigator and a small subset of those data will be used to test our ability to identify high risk variants for actionable disorders, coupled to knowledgeable clinical interpretation, genetic counseling and referral for ongoing care. The human subjects review and approval of the gene identification research use of the exome data will be addressed by the approved PIs through their own IRBs. Here, we are requesting review of the generation of the sequence data by next-gen technology for secondary variants, a bioinformatic pipeline for filtering those variants, manual curation of the variants, and behavioral follow up of participants who receive secondary findings results to measure their utility and perceived value. Additional and critical Specific Aims are to measure the efficacy by which we communicate 1) to the participants who do not receive a secondary finding the concept that a secondary findings analysis is not a substitute for an indicated single gene and 2) explore the interpretation and outcomes of results for those who receive a secondary finding.