Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)

Purpose: Copy-number analysis to detect disease-causing losses and gainsacross the genome is recommended for the evaluation of individuals withneurodevelopmental disorders and/or multiple congenital anomalies, as well asfor fetuses with ultrasound abnormalities. In the decade that this analysis hasbeen in widespread clinical use, tremendous strides have been made inunderstanding the effects of copy-number variants (CNVs) in both affectedindividuals and the general population. However, continued broad implementationof array and next-generation sequencing–based technologies will expand the typesof CNVs encountered in the clinical setting, as well as our understanding oftheir impact on human health. Methods: To assist clinical laboratories in the classification and reportingof CNVs, irrespective of the technology used to identify them, the AmericanCollege of Medical Genetics and Genomics has developed the followingprofessional standards in collaboration with the National Institutes of Health(NIH)–funded Clinical Genome Resource (ClinGen) project. Results: This update introduces a quantitative, evidence-based scoringframework; encourages the implementation of the five-tier classification systemwidely used in sequence variant classification; and recommends “uncoupling” theevidence-based classification of a variant from its potential implications for aparticular individual. Conclusion: These professional standards will guide the evaluation ofconstitutional CNVs and encourage consistency and transparency across clinicallaboratories.