A comment to this article is available online at https://doi.org/10.1038/s41436-021-01141-w. This points to consider (PTC) explores the opportunities and challenges presented by exome and genome sequencing (ES/GS) for apparently healthy individuals to inform a genetic predisposition to a disease or disorder. Although the use of DNA-based assays such as ES/GS has become well established in clinical care,1.Abul-Husn N.S. et al.Genetic identification of familial hypercholesterolemia within a single U.S. health care system.2800801010.1126/science.aaf70001:CAS:528:DC%2BC28XitFCntbbN28008010Science. 2016; 354: aaf7000Google Scholar the potential to inform diagnosis, prognosis, treatment, and prevention of disease in the absence of a clinical indication is an active area of study but remains unproven.1.Abul-Husn N.S. et al.Genetic identification of familial hypercholesterolemia within a single U.S. health care system.2800801010.1126/science.aaf70001:CAS:528:DC%2BC28XitFCntbbN28008010Science. 2016; 354: aaf7000Google Scholar, 2.Dewey F.E. et al.Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study.2800800910.1126/science.aaf68141:CAS:528:DC%2BC28XitFCntbbMScience. 2016; 354: aaf6814Google Scholar, 3.Perkins B.A. et al.Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.1:CAS:528:DC%2BC1cXht1GqsbrJ29555771588962210.1073/pnas.1706096114Proc. Natl. Acad. Sci. U. S. A. 2018; 115: 3686-3691Google Scholar, 4.Vassy J.L. et al.The impact of whole-genome sequencing on the primary care and outcomes of healthy adult patients: a pilot randomized trial.28654958585665410.7326/M17-0188Ann. Intern. Med. 2017; 167: 159-169Google Scholar Clinical practice, research studies, and consumer-directed commercial offerings allow greater availability to ES/GS data than ever before, although with noted differences in uptake based on demographic factors.5.Crawford D.C. Cooke Bailey J.N. Briggs F.B.S. Mind the gap: resources required to receive, process and interpret research-returned whole genome data.31161416676790510.1007/s00439-019-02033-5Hum. Genet. 2019; 138: 691-701Google Scholar,6.Roberts M.C. Mensah G.A. Khoury M.J. Leveraging implementation science to address health disparities in genomic medicine: examples from the field.30906168642817410.18865/ed.29.S1.187Ethn. Dis. 2019; 29: 187-192Google Scholar It is important to consider how this emerging shift toward greater availability of ES/GS testing will change genomic medicine. The American College of Medical Genetics and Genomics (ACMG) has generated this PTC document to guide individuals and health-care providers who are considering undertaking DNA-based health screening. Those leading programs and sponsoring organizations who are providing DNA-based screening are encouraged to review the ACMG document on DNA-based screening and population health for addition points to consider.7.Murray, M. F. et al. DNA-based screening and population health: a points to consider document for programs and sponsoring organizations from the American College of Medical Genetics and Genomics (ACMG). Genet. Med.https://doi.org/10.1038/s41436-020-01082-w.Google Scholar The ACMG seeks to promote the most effective use of genetic and genomic information by offering this PTC document that may help guide discussions about potential benefits, potential harms, and limitations of ES/GS for healthy adults through each essential step in the testing process. Current models for delivery of genetic testing services include a traditional genetic health-care model of coordinated services between genetics health-care providers and a patient’s referring primary care provider and a nontraditional genetic health-care model where genetic services are integrated within primary care and other specialties.8.Battista R.N. Blancquaert I. Laberge A.M. van Schendel N. Leduc N. Genetics in health care: an overview of current and emerging models.1:STN:280:DC%2BC3MbnvVSisA%3D%3D2173435710.1159/000328846Public Health Genomics. 2012; 15: 34-45Google Scholar We have also considered another model, an emerging consumer-directed genetic health-care model in which consumers initiate the genomic medicine process on their own without direction from a health-care provider. A framework for the delivery of molecular genetic tests according to the preanalytical, analytical, and postanalytical phases of the genetic testing process has been described.9.Chen B. et al.Good laboratory practices for molecular genetic testing for heritable diseases and conditions.19521335MMWR Recomm. Rep. 2009; 58 (quiz CE-31–4): 1-37Google Scholar While the actions performed for each step involved in delivery of genetic testing services will vary, in general, all steps should occur for any clinical scenario. Therefore, we will consider opportunities and challenges for each step in the testing process for each health-care model as well as forward-looking strategies to address them. Of particular focus is the likely shift to the emerging approach of consumers seeking ES/GS on their own (the consumer-directed model). For each step in the testing process, the accompanying text provides brief considerations as background (usually describing the current state) and strategies for maintaining clinical standards while moving to a wider variety of genetic health-care models. Exome and genome sequencing (ES/GS) refers to the methodologies currently used to carry out large-scale DNA sequencing: either the coding region (exome) following a capture procedure or all genome sequence. Other commonly used terms include whole exome sequencing (WES), whole genome sequencing (WGS), and genomic sequencing. An ES/GS screening test, as opposed to a diagnostic test, refers to the use of ES/GS as a clinical test to assess genotypes that identify individuals at risk for:•Recessive or X-linked carrier status,•Dominant or recessive Mendelian disease with variable penetrance or later onset,•Pharmacogenomic drug response,•Polygenic risk score for susceptibility to multifactorial disease. In this document, a clinical ES/GS screening test will refer to the ES/GS test performed for an individual in whom ES/GS is not clinically indicated by currently accepted standards, but the results are intended to inform medical decision-making. This testing paradigm has also been referred to as “elective ES/GS testing.”10.Lu J.T. et al.Evaluation for genetic disorders in the absence of a clinical indication for testing: elective genomic testing.3045305710.1016/j.jmoldx.2018.09.006J. Mol. Diagn. 2019; 21: 3-12Google Scholar A clinical ES/GS test will refer to the assay itself performed in a CLIA-certified laboratory. In this context, the term “screening” is being applied to indicate that the test is not being done for a specific symptomatic presentation or for a specific indication, but is being done to determine risk for future medical use. An ES/GS screening test may be motivated by many factors such as curiosity, personal or family history of a genetic disorder that does not meet guidelines for diagnostic testing, concern of not knowing family history, or desire to know future health or reproductive risks. We also recognize the ambiguity associated with an attempt to distinguish a screening test from an indication-based diagnostic test, when both may be used to direct clinical care. The models for delivery of genetic health care, including genetic testing, include:•A traditional genetic health-care model: coordinated services between geneticists and other physicians.8.Battista R.N. Blancquaert I. Laberge A.M. van Schendel N. Leduc N. Genetics in health care: an overview of current and emerging models.1:STN:280:DC%2BC3MbnvVSisA%3D%3D2173435710.1159/000328846Public Health Genomics. 2012; 15: 34-45Google Scholar•A nontraditional genetic health-care model: genetic testing is ordered and managed within primary care and other specialties.8.Battista R.N. Blancquaert I. Laberge A.M. van Schendel N. Leduc N. Genetics in health care: an overview of current and emerging models.1:STN:280:DC%2BC3MbnvVSisA%3D%3D2173435710.1159/000328846Public Health Genomics. 2012; 15: 34-45Google Scholar•An emerging consumer-directed genetic health-care model: consumers access genetic services on their own without direction from their personal health-care provider. This model may utilize physicians employed by the testing service to order the testing, but who do not take long-term responsibility for medical management of the consumer. This document focuses on the emerging state of clinical ES/GS screening tests performed on apparently healthy individuals to inform individualized options for early disease detection, disease prevention, targeted treatments, and reproductive decisions. Variants associated with nutritional status, ancestry, or other non–medically relevant phenotype traits and ancestry will not be discussed. Other technologies such as chromosomal microarray or G-banded chromosome analysis, as well as more limited sequencing assays such as gene panels, will not be discussed. However, if such analyses were requested as a screening test, then the same basic concepts would apply. There are additional clinical and ethical considerations in the potential use of clinical ES/GS screening in minors, particularly for adult-onset conditions. This PTC will pertain to ES/GS in the healthy adult. To explore the future of ES/GS screening tests, certain assumptions were made:•The demand for ES/GS screening tests by consumers will continue to increase.•Regulatory agencies will not prohibit consumer-directed genetic health care, enabling expansion of ES/GS screening test availability.•Laboratories performing ES/GS screening tests will all be held to the same standards regardless of which genetic health-care model is accessed.•The cost of the ES/GS screening test will be paid by the patient/consumer or for the patient/consumer by another entity such as their health insurer or employer, regardless of how the test is ordered. For each of the genetic health-care models, we describe the potential challenges and opportunities of ES/GS screening related to the preanalytical phase (Table 1), the analytical phase (Table 2), and the postanalytical phase (Table 3). Below we summarize these challenges and opportunities and also provide some strategies that could address those challenges and leverage opportunities.Table 1Preanalytical challenges and opportunities in genomic screening of apparently healthy individuals. Open table in a new tab Table 2Analytical challenges and opportunities in genomic screening of apparently healthy individuals. Open table in a new tab Table 3Postanalytical challenges and opportunities in genomic screening of apparently healthy individuals. Open table in a new tab Under the traditional model, genetics professionals, knowledgeable about genetic principles underlying disease and health, are able to identify the optimum strategy for establishing a genetic diagnosis or genetic contribution to disease, which typically includes a comprehensive review of an individual’s medical history and family history with pedigree analysis to assess possible modes of inheritance. They also provide genetic counseling and patient education techniques to appreciate and integrate an individual’s genetic literacy, beliefs, and preferences. However, the time required for a typical clinical encounter under the traditional genetic health-care model is not scalable, given the limited number of genetics health-care providers. Under the nontraditional model, while primary care providers and other specialists may have less expertise in genetics,11.Bensend T.A. Veach P.M. Niendorf K.B. What’s the harm? Genetic counselor perceptions of adverse effects of genetics service provision by nongenetics professionals.2375450610.1007/s10897-013-9605-3J. Genet. Couns. 2014; 23: 48-63Google Scholar, 12.Heck P.R. Meyer M.N. Population whole exome screening: primary care provider attitudes about preparedness, information avoidance, and nudging.3158200510.1016/j.mcna.2019.08.004Med. Clin. North Am. 2019; 103: 1077-1092Google Scholar, 13.Carroll J.C. et al.Informing integration of genomic medicine into primary care: an assessment of current practice, attitudes, and desired resources.31824576688228210.3389/fgene.2019.01189Front. Genet. 2019; 10: 1189Google Scholar they may be more readily available to provide ES/GS screening tests than genetics providers. Additionally, they are likely to be familiar with the health status, preferences, and medical literacy of a patient, and are trained to deal with complex medical issues and seek expert genetics consultation, as needed. In a consumer-directed health-care model, consumers can seek out information and resources that suit their perceived needs at a convenient time and without having to participate in a clinical encounter. The capacity for a consumer to seek out information about an ES/GS screening test is limited only by their own time, interest, and the availability of reliable and understandable information from consumer-directed testing entities. Each genetic health-care model must appreciate the wide range of medical and technical literacy of consumers and patients.5.Crawford D.C. Cooke Bailey J.N. Briggs F.B.S. Mind the gap: resources required to receive, process and interpret research-returned whole genome data.31161416676790510.1007/s00439-019-02033-5Hum. Genet. 2019; 138: 691-701Google Scholar,6.Roberts M.C. Mensah G.A. Khoury M.J. Leveraging implementation science to address health disparities in genomic medicine: examples from the field.30906168642817410.18865/ed.29.S1.187Ethn. Dis. 2019; 29: 187-192Google Scholar Genetics professionals and other health-care providers are trained to educate and transfer knowledge to patients in an individualized medical context, whereas the consumer-directed model relies on the consumer to navigate through the available information and identify what is most relevant for them. Greater availability of ES/GS screening tests will necessitate the development of effective educational materials that teach genetic/genomic principles and aid in test interpretation aimed at a variety of education levels. These educational materials will be of particular importance for both the nontraditional health-care model and the consumer-directed model. The nontraditional model can benefit from decision support tools in the electronic health record that assist the nongeneticist clinician in obtaining consent and performing genetic risk assessment, identifying indications for genetic testing, interpreting test results, and making management recommendations.14.Scheuner M.T. et al.A cancer genetics toolkit improves access to genetic services through documentation and use of the family history by primary-care clinicians.2376505110.1038/gim.2013.75Genet. Med. 2014; 16: 60-69Google Scholar, 15.Shickh S. et al.Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial.29700101592251610.1136/bmjopen-2018-021876BMJ Open. 2018; 8: e021876Google Scholar, 16.Schmidlen T. Schwartz M. DiLoreto K. Kirchner H.L. Sturm A.C. Patient assessment of chatbots for the scalable delivery of genetic counseling.3154975810.1002/jgc4.1169J. Genet. Couns. 2019; 28: 1166-1177Google Scholar Genetics health-care professionals will be instrumental in developing these novel tools to efficiently and effectively communicate information and educate patients. Access to such experts via telemedicine could further reduce resource gaps.17.Vrecar I. Hristovski D. Peterlin B. Telegenetics: an update on availability and use of telemedicine in clinical genetics service.2798715810.1007/s10916-016-0666-3J. Med. Syst. 2017; 41Google Scholar Professional organizations have consistently endorsed an informed consent process prior to germline genetic testing to review the potential benefits, harms, and limitations of testing, including the implications of results for the patient and their family member.18.American Society of Clinical Oncology American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.10.1200/JCO.2003.03.189J. Clin. Oncol. 2003; 21: 2397-2406Google Scholar,19.ACMG Board of Directors Points to consider for informed consent for genome/exome sequencing.10.1038/gim.2013.94Genet. Med. 2013; 15: 748-749Google Scholar Generally accepted and expected elements of informed consent for germline genetic testing include ensuring an understanding of:•Indications and limitations of the testing.•Possible outcomes of the testing.•Implications of results for the tested individual and their relatives (e.g., potential benefits and risks).•Ethical considerations (e.g., testing children).•How to access genetic resources when needed (e.g., medical geneticist, genetic counselor, advocacy organizations). Individuals undergoing genomic testing report benefit from pretest counseling.20.Suckiel S.A. et al.Impact of genomic counseling on informed decision-making among ostensibly healthy individuals seeking personal genome sequencing: the HealthSeq Project.2689868010.1007/s10897-016-9935-zJ. Genet. Couns. 2016; 25: 1044-1053Google Scholar Irrespective of the mode of care in which ES/GS screening tests are performed, the essential elements of informed consent must be accomplished. However, informed consent for an ES/GS screening test might be best accomplished with a member of the individual’s primary care team, who is knowledgeable about their medical problems, beliefs, and preferences. Under the consumer-directed model, informed consent processes may be less standardized and comprehensive,21.Niemiec E. Borry P. Pinxten W. Howard H.C. Content analysis of informed consent for whole genome sequencing offered by direct-to-consumer genetic testing companies.2764780110.1002/humu.23122Hum. Mutat. 2016; 37: 1248-1256Google Scholar which raises concerns for the consent process, especially among vulnerable populations. The potential harms associated with the ES/GS screening test are different from those associated with diagnostic testing, and the consent process must address these special concerns (Table 2). For diagnostic testing, personal and family history is collected before genetic testing is offered to inform the indication and appropriateness of testing, differential diagnosis, mode of inheritance, and testing strategy. Under any of the health-care models, whoever is ordering the ES/GS screening test should ensure the patient/consumer gains sufficient understanding of the potential benefits and harms to make an informed decision about pursuing the testing. Ideally, with an ES/GS screening test, the complexities of potential test results that should be understood include:•The potential positive and negative impact of ES/GS screening test results and their implications for family members.•Awareness that the laws protecting genetic privacy and nondiscrimination are not comprehensive, and that those that do exist have not been fully tested; some groups may not be protected by existing laws.•Lifetime disease risks are often not known, including penetrance and variable expressivity of a pathogenic variant.•A false negative result: A person may be at risk for a health problem not identified by the ES/GS test due to technical (a pathogenic variant is present but not detected) or interpretive error (a pathogenic variant is interpreted as benign) or because not all gene–disease associations are known.•A false positive result: A person may not be at risk for a health problem suggested by the ES/GS screening test results due to technical (a reported pathogenic variant is not actually present) or interpretive error (a benign variant is interpreted as pathogenic).•Evolving interpretation: The results of a genetic test may indicate risk for disease; however, the clinical significance of variants, gene–disease associations, penetrance of pathogenic variants, and opportunities for clinical interventions can change with time.•Evidence to support clinical actions based on ES/GS findings may not be available.•Results may indicate a need for a medical evaluation, preventive services, or ongoing surveillance; however, access to health care may be limited or restricted due to out-of-pocket costs or lack of insurance.•Options for the type of genetic test result to be reported such as carrier status for recessive conditions, adult-onset medically actionable or nonactionable findings, pharmacogenomics results. Importantly, patients or consumers seeking an ES/GS screening test may self-select due to an enriched family history or subtle phenotypes such that they should be pursuing an indication-based test or population-targeted test, but instead pursue a screening non-indication-based test.22.Butterfield R.M. et al.Returning negative results to individuals in a genomic screening program: lessons learned.2987542610.1038/s41436-018-0061-1Genet. Med. 2019; 21: 409-416Google Scholar,23.Zoltick E.S. et al.Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium.30808425639182510.1186/s13073-019-0619-9Genome Med. 2019; 11Google Scholar Therefore, it is vital for any consent process to ensure that screening questions for medical and family history that could indicate the need for diagnostic testing pursued through a health-care provider have been asked, either previously or as part of the pretest counseling. Additionally, the informed consent process should review data ownership and secondary uses of the ES/GS screening tests (see preanalytical step 3). Programs such as JScreen, a national Jewish genetic disease screening program,24.Grinzaid K.A. Page P.Z. Denton J.J. Ginsberg J. Creation of a national, at-home model for Ashkenazi Jewish carrier screening.2550200310.1007/s10897-014-9800-xJ. Genet. Couns. 2015; 24: 381-387Google Scholar All of Us,25.National Institutes of Health. All of Us research program. http://allofus.nih.gov (2020).Google Scholar and the ClinGen Consent and Disclosure Recommendations (CADRe) Workgroup26.Ormond K.E. et al.Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background.1:CAS:528:DC%2BC1cXhtlWns7bI2997698810.1038/s41436-018-0093-6Genet. Med. 2019; 21: 727-735Google Scholar use materials developed by genetics experts to allow self-education by individuals interested in genetic testing that support informed consent. The JScreen program includes assessment of understanding as part of the consent process with follow-up (phone call or mailed report) dependent on result and mastery of the material. The All of Us consent process uses a series of short videos to explain each part of the process. Online decision aid tools developed for research or clinical use have been described27.Adam S. et al.Assessing an interactive online tool to support parents’ genomic testing decisions.10.1007/s10897-018-0281-1J. Genet. Couns. 2019; 28: 10-17Google Scholar and could be used in an ES/GS screening test consent process in any of the genetic health-care models, but may be ideal for the consumer-driven model. It would be best to have input from genetics experts to help guide the informed consent process under the nontraditional and consumer-directed health-care models. Regulators will need to determine what constitutes adequate informed consent in the consumer-directed model and how these standards compare with the requirements of the health-care models. Data and residual specimens from ES/GS screening tests may be used for many purposes beyond their intended use, including gathering data for variant interpretation, identification of risk alleles, drug development, and discovery; therefore, these data have collective value. Third parties (employers, health-care systems, researchers, commercial entities) may be interested in these data for reasons such as aggregate analysis of population characteristics, development of marketable products, and sale or sharing of the data. Current practice has moved toward individuals having a right to access their medical records28.Vermeir P. et al.The patient perspective on the effects of medical record accessibility: a systematic review.2805666510.1080/17843286.2016.1275375Acta Clin. Belg. 2017; 72: 186-194Google Scholar and their personal data, including genomic data from research participation.29.Jarvik G.P. et al.Return of genomic results to research participants: the floor, the ceiling, and the choices in between.1:CAS:528:DC%2BC2cXnslGnsLk%3D24814192412147610.1016/j.ajhg.2014.04.009Am. J. Hum. Genet. 2014; 94: 818-826Google Scholar,30.Wolf S.M. et al.Managing incidental findings and research results in genomic research involving biobanks and archived data sets.22436882359734110.1038/gim.2012.23Genet. Med. 2012; 14: 361-384Google Scholar Many research projects require that genomic results be returned to participants when requested, including the All of Us program; however, protocols for returning such complex data to a diverse group of people with varying technical literacy have not been established.5.Crawford D.C. Cooke Bailey J.N. Briggs F.B.S. Mind the gap: resources required to receive, process and interpret research-returned whole genome data.31161416676790510.1007/s00439-019-02033-5Hum. Genet. 2019; 138: 691-701Google Scholar,6.Roberts M.C. Mensah G.A. Khoury M.J. Leveraging implementation science to address health disparities in genomic medicine: examples from the field.30906168642817410.18865/ed.29.S1.187Ethn. Dis. 2019; 29: 187-192Google Scholar Expansion of ES/GS screening tests performed under any model will be governed by HIPAA and CLIA requirements and will require regulatory oversight for ownership, storage, and use of the data beyond their intended clinical purpose. Therefore, data storage approaches that are affordable, accessible, interoperable, and secure must be developed. Laboratories currently performing an ES/GS test that is intended to be returned to patients/consumers for any clinical purposes must hold a CLIA license. Commercialization of ES/GS screening tests may move testing away from genetic testing laboratories that perform clinical diagnostic testing under the traditional and nontraditional genetic health-care models to laboratories that cater to consumer-directed testing. Some payers may limit coverage to laboratories that share their data as a means of ensuring ongoing test result interpretation. Laboratories may freely share their data with various resources used by genetics professionals (e.g., ClinVar, GeneMatcher) or receive reimbursement for sharing data with a third party. Educational and consent materials for health-care providers and consumers will be different; therefore, a laboratory may need to provide different services depending on the health-care model. Factors influencing laboratory choice and ability to evaluate laboratory quality will likely vary among health-care models (Table 1). ES/GS testing becoming a primarily cost-driven commodity is a concern since the focus would be shifted away from patient care. Regulatory requirements for disclosure of a standard set of metrics that could include information on licensure held, laboratory leadership, professional guidelines followed, qualifications of staff, billing and cost structure, as well as clear disclosure as to whether the test is intended to be used for medical purposes, as opposed to recreational purposes, would allow transparent comparison among laboratories. Additionally, laboratories may need to meet new requirements for education and consent to offer consumer-directed testing. The extent to which the laboratory is responsible for the patient’s/consumer’s understanding of the ES/GS screening test purpose and results needs to be established. Genomic data intended to be disclosed for medical purposes must be generated in CLIA-licensed laboratories. Critical information about the test performed, such as details about the methodology used, scope of testing performed, and limitations at the time of testing should be available for both pre- and post-test review. Optimal interpretations of ES/GS results are based on evaluations by board-certified individuals with appropriate training in medical genetics to interpret genomic data.31.ACMG Board of Directors Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG).10.1038/gim.2014.761:CAS:528:DC%2BC2MXmslegsw%3D%3DGenet. Med. 2015; 17: e3Google Scholar All testing should be performed in accordance with relevant regulatory requirements and professional standards. Therefore, unlike other steps in the testing process, the opportunities and challenges are the same for each of the genetic health-care models. Laboratories following current regulatory requirements confirm that testing is ordered by a qualified health-care provider. As a consumer-directed market for ES/GS testing emerges, changes in regulatory requirements to accommodate this model will be needed. Analytical sensitivity of ES/GS testing is high, but also uneven across the genome with some areas of clinical relevance more difficult to sequence than others.32.Bean L.J.H. et al.Diagnostic gene sequencing panels: from design to report-a technical standard of the American College of Medical Genetics and Genomics (ACMG).3173271610.1038/s41436-019-0666-zGenet. Med. 2020; 22: 453-461Google Scholar Some types of abnormalities are less likely or not able to be detected by ES/GS than by other technologies, such as copy-number variants, tandem repeats, and methylatio