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).

Riggs ER1, Andersen EF2,3, Cherry AM4, Kantarci S5, Kearney H6, Patel A7, Raca G8, Ritter DI9, South ST10, Thorland EC6, Pineda-Alvarez D11, Aradhya S4,11, Martin CL12.

Author information

1: Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA. documents@acmg.net.
2: ARUP Laboratories, Salt Lake City, UT, USA.
3: Department of Pathology, University of Utah, Salt Lake City, UT, USA.
4: Stanford University School of Medicine, Stanford, CA, USA.
5: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA, USA.
6: Genomics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
7: Lineagen, Salt Lake City, UT, USA.
8: Children's Hospital Los Angeles, Los Angeles, CA, USA.
9: Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
10: AncestryDNA, Lehi, UT, USA.
11: Invitae, San Francisco, CA, USA.
12: Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA.

Abstract

PURPOSE:

Copy-number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy-number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health.

METHODS:

To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen) project.

RESULTS:

This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the five-tier classification system widely used in sequence variant classification; and recommends "uncoupling" the evidence-based classification of a variant from its potential implications for a particular individual.

CONCLUSION:

These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.