28. Standards for the classification and reporting of constitutional copy number variants: A ClinGen/ACMG joint consensus recommendation

To assist clinical laboratories in performing consistent, transparent classification of constitutional CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics (ACMG), in collaboration with the NIH-funded Clinical Genome Resource (ClinGen) project, has updated existing professional standards. While the existing ACMG guidelines provide a high-level conceptual framework for evaluating constitutional CNVs in diagnostic testing, this proposed update will provide point-based, hierarchical scoring systems for both copy number losses and copy number gains to systematically evaluate relevant evidence. Multiple categories are used to help interpret CNVs including: overlap with CNVs reported in clinically affected individuals, overlap with CNVs reported in unaffected individuals, case-control studies, the presence of known dosage-sensitive genes, case reports with segregation data, de novo occurrence of CNVs, and the number of protein-coding genes included in the CNV. These metrics were tested on a set of 111 CNVs previously evaluated by clinical genetic laboratories. Each CNV was evaluated by 2 independent reviewers. Using the metrics, reviewers came to concordant classifications 73.0% of the time. Other significant updates include implementing a 5-tier classification system parallel to that used for interpreting sequence variants, and the recommendation to uncouple the evidence-based classification of a variant from its potential implications for a particular individual (i.e., not using clinical context to justify classifying the same variant differently in different individuals). These updated standards will have broad impact in the clinical community by providing a robust system to support the consistent classification of CNVs.