Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research. We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability. We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders. The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258-1268.

As genome-scale sequencing is increasingly applied in clinical scenarios, a wide variety of genomic findings will be discovered as secondary or incidental findings, and there is debate about how they should be handled. The clinical actionability of such findings varies, necessitating standardized frameworks for a priori decision making about their analysis. We established a semiquantitative metric to assess five elements of actionability: severity and likelihood of the disease outcome, efficacy and burden of intervention, and knowledge base, with a total score from 0 to 15. The semiquantitative metric was applied to a list of putative actionable conditions, the list of genes recommended by the American College of Medical Genetics and Genomics (ACMG) for return when deleterious variants are discovered as secondary/incidental findings, and a random sample of 1,000 genes. Scores from the list of putative actionable conditions (median = 12) and the ACMG list (median = 11) were both statistically different than the randomly selected genes (median = 7) (P < 0.0001, two-tailed Mann-Whitney test). Gene-disease pairs having a score of 11 or higher represent the top quintile of actionability. The semiquantitative metric effectively assesses clinical actionability, promotes transparency, and may facilitate assessments of clinical actionability by various groups and in diverse contexts.Genet Med 18 5, 467-475.

Purpose: Advances in clinical genomic sequencing capabilities, including reduced costs and knowledge gains, have bolstered the consideration of genomic screening in healthy adult populations. Yet, little is known about the existing landscape of genomic screening programs in the United States. It can be difficult to find information on current implementation efforts and best practices, particularly in light of critical questions about equity, cost, and benefit. Methods: In 2020, we searched publicly available information on the Internet and the scientific literature to identify programs and collect information, including: setting, program funding, targeted population, test offered, and patient cost. Program representatives were contacted throughout 2020 and 2021 to clarify, update, and supplement the publicly available information. Results: Twelve programs were identified. Information was available on key program features, such as setting, genes tested, and target populations. Data on costs, outcomes, or long-term sustainability plans were not always available. Most programs offered testing at no or significantly reduced cost due to generous pilot funding, although the sustainability of these programs remains unknown. Gene testing lists were diverse, ranging from 11 genes (CDC tier 1 genes) to 59 genes (ACMG secondary findings list v.2) to broad exome and genome sequencing. This diversity presents challenges for harmonized data collection and assessment of program outcomes. Conclusions: Early programs are exploring the logistics and utility of population genomic screening in various settings. Coordinated efforts are needed to take advantage of data collected about uptake, infrastructure, and intervention outcomes to inform future research, evaluation, and program development.

Aims: Pharmacogenetic (PGx) tests are intended to improve therapeutic outcomes through predicting a patient's likelihood to respond to or experience an adverse effect from a specific treatment. In addition, PGx testing may also generate ancillary, or incidental, disease information unrelated to the purpose for which the test was ordered. To assess public attitudes toward PGx testing, ancillary disease risk information and related clinical issues, we conducted a series of focus groups. Results: Forty-five individuals recruited from Durham, NC, participated in four focus groups. Overall, participants were enthusiastic about PGx testing, though expressed concerns about privacy, confidentiality, and psychological harms associated with ancillary information. Focus group participants believed that physicians had a responsibility to disclose ancillary risk information, but were concerned about managing and coping with unexpected disease risk information. Conclusion: We find that participants welcomed the integration of PGx testing into therapeutic decision-making. Public concerns about PGx testing and ancillary information specifically centered on personal implications of learning such additional information, suggesting that patient–provider discussion of the benefits and risks of testing will be necessary until public familiarity with these tests increases.

Aims: Pharmacogenetic (PGx) tests, intended to inform therapeutic decision making through prediction of patient likelihood to respond to or experience an adverse effect from a specific treatment, may also generate ancillary, or incidental, disease information unrelated to the purpose for which the test was ordered. To assess attitudes toward PGx testing, ancillary disease risk information, and related clinical issues, we conducted a series of focus groups among health professionals. Results: Twenty-one primary care and genetics professionals from Durham, NC, were recruited to participate in three focus groups (two of primary care professionals [PCPs] and one of geneticists). Overall, interest in PGx testing was positive, though enthusiasm was reserved among PCPs due to concerns about clinical utility, insurance coverage, delay of treatment, and ability to communicate and interpret ancillary disease risk information. Although many PCPs felt an obligation to disclose information about ancillary disease risk, geneticists did not believe that it was always necessary, noting the complexities of genetic risk results such as incomplete penetrance. Conclusion: This pilot study found that health professionals' interest in the use of PGx testing was limited by concerns about the lack of evidence of clinical utility and their ability to interpret and communicate ancillary disease risk information to patients. Additional educational resources, access to genetic specialists, and clear clinical guidelines about the use of PGx testing would greatly facilitate appropriate use of testing.