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).
Miller, D. T. 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. https://doi.org/10.1038/s41436-021-01171-4 (2021).
Clinical Genome Resource. https://clinicalgenome.org/ (2018).
eMERGE Consortium. Harmonizing clinical sequencing and interpretation for the eMERGE III Network. Am. J. Hum. Genet. 105, 588–605 (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).
ACMG. Secondary findings nomination form. https://www.acmg.net/PDFLibrary/Secondary-Findings-Panel-Nomination-Form.pdf (2021).
Yang, X. et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J. Clin. Oncol. 38, 674–685 (2020).
Kim, J. et al. Frequency of pathogenic germline variants in cancer-susceptibility genes in the Childhood Cancer Survivor Study. JNCI Cancer Spectrum 5, pkab007 (2021). https://doi.org/10.1093/jncics/pkab007.
Tischkowitz, M. et al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. https://doi.org/10.1038/s41436-021-01151-8. (In press).
Else, T., Greenberg, S. & Fishbein, L. in GeneReviews (eds Adam, M. P. et al.) Hereditary paraganglioma–pheochromocytoma syndromes. (University of Washington, Seattle, 2018).
Bausch, B. et al. Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncol. 3, 1204–1212 (2017).
Hershberger, R. E. et al. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J. Card. Fail. 24, 281–302 (2018).
Al-Khatib, S. M. et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 138, e272–e391 (2018).
Ortiz-Genga, M. F. et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J. Am. Coll. Cardiol. 68, 2440–2451 (2016).
Verdonschot, J. A. J. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum. Mutat. 41, 1091–1111 (2020).
Ader, F. et al. FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations. Clin. Genet. 96, 317–329 (2019).
Haggerty, C. M. et al. Genomics-first evaluation of heart disease associated with titin-truncating variants. Circulation. 140, 42–54 (2019).
HRSA. Newborn screening: toward a uniform screening panel and system. https://www.hrsa.gov/sites/default/files/hrsa/advisory-committees/heritable-disorders/newborn-uniform-screening-panel.pdf (2020).
Lloyd-Puryear, M., Brower, A., Berry, S. A., Brosco, J. P., Bowdish, B. & Watson, M. S. Foundation of the Newborn Screening Translational Research Network and its tools for research. Genet. Med. 21, 1271–1279 (2019).
Clinical Genome Resource Actionability Working Group. Biotinidase deficiency summary report. https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC098 (2020).
Wolf, B. in GeneReviews (eds Adam, M. P. et al.) Biotinidase deficiency. (University of Washington, Seattle, 2018).
NewSTEPs. Newborn screening status for all disorders. https://www.newsteps.org/resources/data-visualizations/newborn-screening-status-all-disorders (2020).
Clinical Genome Resource Actionability Working Group. Glycogen storage disease II summary report. https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC090 (2019).
Leslie, N. & Bailey, L. in GeneReviews (eds Adam, M. P. et al.) Pompe disease. (University of Washington, Seattle, 2018).
Germain, D. P. et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease. J. Med. Genet. 52, 353–358 (2015).
Wilcox, W. R. et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol. Genet. Metab. 93, 112–128 (2008).
Clinical Genome Resource Actionability Working Group. X-linked adrenoleukodystrophy summary report. https://actionability.clinicalgenome.org/ac/Adult/ui/stg2SummaryRpt?doc=AC117 (2019).
Raymond, G. V., Moser, A. B. & Fatemi, A. in GeneReviews (eds Adam, M. P. et al.) X-linked adrenoleukodystrophy. (University of Washington, Seattle, 2018).
McDonald, J. & Pyeritz, R. E. in GeneReviews (eds Adam, M. P. et al.) Hereditary hemorrhagic telangiectasia. (University of Washington, Seattle, 2018).
Wooderchak-Donahue, W. L. et al. BMP9 mutations cause a vascular-anomaly syndrome with phenotypic overlap with hereditary hemorrhagic telangiectasia. Am. J. Hum. Genet. 93, 530–537 (2013).
Girerd, B. et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am. J. Respir. Crit. Care Med. 181, 851–861 (2010).
Austin, E. D., Loyd, J. E. & Phillips, J. A. III in GeneReviews (eds Adam, M. P. et al.) Heritable pulmonary arterial hypertension overview. (University of Washington, Seattle, 2018).
Garcia-Rivas, G., Jerjes-Sánchez, C., Rodriguez, D., Garcia-Pelaez, J. & Trevino, V. A systematic review of genetic mutation in pulmonary arterial hypertension. BMC Med. Genet. 18, 82 (2017).
Vorselaars, V. M. M. et al. Pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Int. J. Mol. Sci. 19, 3203 (2018).
Naylor, R., Knight Johnson, A. & del Gaudio, D. in GeneReviews (eds Adam, M. P. et al.) Maturity-onset diabetes of the young overview. (University of Washington, Seattle, 2018).
Bellanne-Chantelot, C. et al. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 54, 3126–3132 (2005).
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).
Barton, J. C. & Edwards, C. Q. in GeneReviews (eds Adam, M. P. et al.) HFE hemochromatosis. (University of Washington, Seattle, 2018).
Chao, D. L., Burr, A. & Pennesi, M. in GeneReviews (eds Adam, M. P. et al.) RPE65-related Leber congenital amaurosis/early-onset severe retinal dystrophy. (University of Washington, Seattle, 2018).
Gardiner, K. L. et al. Long-term structural outcomes of late-stage RPE65 gene therapy. Mol. Ther. 28, 266–278 (2020).
Pennesi, M. E. et al. Results at 5 years after gene therapy for RPE65-deficient retinal dystrophy. Hum. Gene Ther. 29, 1428–1437 (2018).
Hicks, J. K. et al. A call for clear and consistent communications regarding the role of pharmacogenetics in antidepressant pharmacotherapy. Clin. Pharmacol. Ther. 107, 50–52 (2020).
Bousman, C. A. et al. Review and consensus on pharmacogenomic testing in psychiatry. Pharmacopsychiatry. 54, 5–17 (2021).
Gonsalves, S. G. et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin. Pharmcol. Ther. 105, 1338–1344 (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. We are also grateful to the ClinGen Actionability Working Group for their evaluations of many of the genes that we reviewed.
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., Chung, W.K. et al. ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med (2021). https://doi.org/10.1038/s41436-021-01172-3