Copy number variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
While many copy number changes observed by chromosomal microarray testing can readily be characterized as pathogenic or benign, there are limited data available to support definitive classification of a subset into either of these categories, making interpretation of these variants challenging. In these situations, a number of considerations are taken into account to help interpret results including the size and gene content of the imbalance, as well as whether the change is a deletion or duplication. Parental testing may also be necessary to further assess the potential pathogenicity of a copy number change. In such situations, the inheritance pattern and clinical and developmental history of the transmitting parent will be taken into consideration.
All copy number variants within the limit of detection classified as pathogenic or likely pathogenic will be reported regardless of size. This includes but is not limited to incidental findings currently recommended for reporting by the American College of Medical Genetics and Genomics (ACMG).(1) Copy number changes with unknown significance will be reported when at least one protein-coding gene is involved in a deletion greater than 1 megabase (Mb) or a duplication greater than 2 Mb.
The detection of excessive homozygosity may suggest the need for additional clinical testing to confirm uniparental disomy (UPD) or to test for variants in genes associated with autosomal recessive disorders consistent with the patient's clinical presentation that are present in regions of homozygosity. Regions with absence of heterozygosity (AOH) of unknown significance will be reported when greater than 5 Mb (terminal) and 10 Mb (interstitial) on UPD-associated chromosomes. Whole genome AOH will be reported when greater than 10% of the genome.
The continual discovery of novel copy number variation and published clinical reports means that the interpretation of any given copy number change may evolve with increased scientific understanding.