Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Green, R. C. et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet. Med. 15, 565–574 (2013).
Kalia, S. S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet. Med. 19, 249–255 (2017).
Scheuner, M. T. et al. Reporting genomic secondary findings: ACMG members weigh in. Genet. Med. 17, 27–35 (2015).
ACMG. Secondary findings nomination form. https://www.acmg.net/PDFLibrary/Secondary-Findings-Panel-Nomination-Form.pdf (2021).
Amendola, L. M. et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 25, 305–315 (2015).
Yang, Y. et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 312, 1870–1879 (2014).
Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696–704 (2016).
Schwartz, M. L. B. et al. A model for genome-first care: returning secondary genomic findings to participants and their healthcare providers in a large research cohort. Am. J. Hum. Genet. 103, 328–337 (2018).
Dewey, F. E. et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 354, aaf6814 (2016).
Van Hout, C. V. et al. Exome sequencing and characterization of 49,960 individuals in the UK Biobank. Nature. 586, 749–756 (2020).
eMERGE Clinical Annotation Working Group. Frequency of genomic secondary findings among 21,915 eMERGE network participants. Genet. Med. 22, 1470–1477 (2020).
Popejoy, A. B. et al. The clinical imperative for inclusivity: Race, ethnicity, and ancestry (REA) in genomics. Hum. Mutat. 39, 1713–1720 (2018).
Popejoy, A. B. et al. Clinical genetics lacks standard definitions and protocols for the collection and use of diversity measures. Am. J. Hum. Genet. 107, 72–82 (2020).
Mackley, M. P., Fletcher, B., Parker, M., Watkins, H. & Ormondroyd, O. Stakeholder views on secondary findings in whole-genome and whole-exome sequencing: a systematic review of quantitative and qualitative studies. Genet. Med. 19, 283–293 (2017).
Delanne, J. et al. Secondary findings from whole-exome/genome sequencing evaluating stakeholder perspectives. A review of the literature. Eur. J. Med. Genet. 62, 103529 (2019).
Darnell, A. J. et al. A clinical service to support the return of secondary genomic findings in human research. Am. J. Hum. Genet. 98, 435–441 (2016).
Wynn, J. et al. Clinical providers’ experiences with returning results from genomic sequencing: an interview study. BMC Med. Genomics. 11, 45 (2018).
Ormondroyd, E. et al. “Not pathogenic until proven otherwise”: perspectives of UK clinical genomics professionals toward secondary findings in context of a Genomic Medicine Multidisciplinary Team and the 100,000 Genomes Project. Genet. Med. 20, 320–328 (2018).
Szego, M. J. et al. Views from the clinic: Healthcare provider perspectives on whole genome sequencing in paediatrics. Eur. J. Med. Genet. 62, 350–356 (2019).
Wilfond, B. S., Fernandez, C. V. & Green, R. C. Disclosing secondary findings from pediatric sequencing to families: considering the “Benefit to Families”. J. Law Med. Ethics. 43, 552–558 (2015).
Hart, M. R. et al. Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study. Genet. Med. 21, 1100–1110 (2019).
Roche, M. I. et al. Factors influencing NCGENES research participants’ requests for non-medically actionable secondary findings. Genet. Med. 21, 1092–1099 (2019).
Robinson, J. O. et al. Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies. Genet. Med. 21, 2781–2790 (2019).
Houdayer, F. et al. Secondary findings from next generation sequencing: psychological and ethical issues. Family and patient perspectives. Eur. J. Med. Genet. 62, 103711 (2019).
Anderson, J. A. et al. Parents perspectives on whole genome sequencing for their children: qualified enthusiasm? J. Med. Ethics. 43, 535–539 (2017).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
ACMG Board of Directors. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 21, 1467–1468 (2019).
ACMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet. Med. 17, 68–69 (2015).
O’Daniel, J. M. et al. A survey of current practices for genomic sequencing test interpretation and reporting processes in US laboratories. Genet. Med. 19, 575–582 (2017).
Ross, L. F., Saal, H. M., David, K. L. & Anderson, R. Technical report: ethical and policy issues in genetic testing and screening of children. Genet. Med. 15, 234–245 (2013).
Monaghan, K. G., Leach, N. T., Pekarek, D., Prasad, P. & Rose, N. C. The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 22, 675–680 (2020).
Sapp, J. C. et al. Evaluation of recipients of positive and negative secondary findings evaluations in a hybrid CLIA-research sequencing pilot. Am. J. Hum. Genet. 103, 358–366 (2018).
eMERGE Consortium. Harmonizing clinical sequencing and interpretation for the eMERGE III Network. Am. J. Hum. Genet. 105, 588–605 (2019).
Batalini, F. et al. Li-Fraumeni syndrome: not a straightforward diagnosis anymore-the interpretation of pathogenic variants of low allele frequency and the differences between germline PVs, mosaicism, and clonal hematopoiesis. Breast Cancer Res. 21, 107 (2019).
Cao, Y. et al. A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. Genome Med. 11, 48 (2019).
Biesecker, L. G. Secondary findings in exome slices, virtual panels, and anticipatory sequencing. Genet. Med. 21, 41–43 (2019).
Biesecker, L. G. Response to Mendelsohn and Sabbadini. Genet. Med. 21, 763 (2019).
Esplin, E. D., Haverfield, E., Yang, S., Aradhya, S. & Nussbaum, R. L. Secondary findings on virtual panels: opportunities, challenges, and potential for preventive medicine. Genet. Med. 21, 1250–1251 (2019).
Biesecker, L. G. Response to Esplin et al. Genet. Med. 21, 1252–1253 (2019).
Rumilla, K. et al. Frequency of deletions of EPCAM (TACSTD1) in MSH2-associated Lynch syndrome cases. J. Mol. Diagn. 13, 93–99 (2011).
Hunter, J. E. et al. A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation. Genet. Med. 18, 1258–1268 (2016).
Webber, E. M. et al. Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen’s Actionability Working Group. Hum. Mutat. 39, 1677–1685 (2018).
Harrison, S. M. & Rehm, H. L. Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar. Genome Med. 11, 72 (2019).
Gallego, C. J. et al. Penetrance of hemochromatosis in HFE genotypes resulting in p.Cys282Tyr and p.[Cys282Tyr];[His63Asp] in the eMERGE Network. Am. J. Hum. Genet. 97, 512–520 (2015).
Grosse, S. D., Gurrin, L. C., Bertalli, N. A. & Allen, K. J. Clinical penetrance in hereditary hemochromatosis: estimates of the cumulative incidence of severe liver disease among HFE C282Y homozygotes. Genet. Med. 20, 383–389 (2018).
Laberge, A. M. Recommending inclusion of HFE C282Y homozygotes in the ACMG actionable gene list: cop-out or stealth move toward population screening? Genet. Med. 20, 400–402 (2018).
Roberts, A. M. et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci. Transl. Med. 7, 270ra6 (2015).
Haggerty, C. M. et al. Genomics-first evaluation of heart disease associated with titin-truncating variants. Circulation. 140, 42–54 (2019).
Pujol, P. et al. Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations. Eur. J. Hum. Genet. 26, 1732–1742 (2018).
Begg, C. B. On the use of familial aggregation in population-based case probands for calculating penetrance. J. Natl. Cancer Inst. 94, 1221–1226 (2002).
Wright, C. F. et al. Assessing the pathogenicity, penetrance, and expressivity of putative disease-causing variants in a population setting. Am. J. Hum. Genet. 104, 275–286 (2019).
We thank members of the original ACMG Incidental Findings Working Group for their groundbreaking efforts to begin the important process of identifying and reporting actionable genetic variants based on genome-scale sequencing. We thank former members of the Secondary Findings Maintenance Working Group for building upon the foundation of the original effort.
S.J.B. is a contractor to GeneDx, a subsidiary of OPKO, through Bale Genetic Consulting, LLC. W.K.C. is a member of the scientific advisory board of Regeneron Genetic Center. D.T.M. has received honoraria from Ambry Genetics and PreventionGenetics LLC. D.R.S. is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute (Rockville, MD), and also performs contract clinical telehealth services for Genome Medical, Inc. in accordance with relevant NCI ethics policies. The other authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
*The Board of Directors of the American College of Medical Genetics and Genomics approved this statement on 22 February 2021.
About this article
Cite this article
Miller, D.T., Lee, K., Gordon, A.S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med (2021). https://doi.org/10.1038/s41436-021-01171-4