In the last few years, the study of CNVs (Copy Number Variations) has acquired great relevance for the postnatal evaluation of individuals with intellectual disability, developmental delay, autism spectrum disorder, and/or multiple congenital anomalies, as well as for fetuses with structural anomalies. However, determining the clinical significance of CNVs is a complex and continuously evolving process that produces different results depending on the laboratory, the technology used and the bioinformatics analysis. These discrepancies make it difficult to validate and interpret them and, consequently, to provide genetic advice to patients.

The American College of Medical Genetics and Genomics in collaboration with Clinical Genome Resource has developed a set of recommendations in order to standardize the evaluation criteria of CNVs, encourage consistency and transparency across clinical laboratories, and lead to improved quality of patient care. These professional standards represent a significant update from previous recommendations but include several major changes. The main change is the incorporation of point-based scoring metric for the most relevant categories to CNVs classification (genomic content, dose-sensitive genes, number of genes, evidence in databases and medical literature, inheritance patterns and family history). To facilitate use of this semiquantitative system, a webbased CNV classification calculator is publicly available. Regarding clinical significance, they use the same five-tier system used for sequence variant classification: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. It is strongly recommended that consistent terminology for these categories be used in clinical reporting to facilitate unambiguous communication of clinical significance throughout the medical community. Finally, they encourage laboratories to uncouple the classification of the variant from the clinical significance. Patient’s phenotype should not override other evidence for or against the pathogenicity of the variant, and it should not be used to justify different classifications of the same variant in different individuals.

These recommendations represent an initial effort for a more consistent interpretation of CNVs, but systematic approach will evolve over time, particularly as knowledge regarding genomic variation and human health improve.

Source: Riggs et al. 2019: Standards for the classification and reporting of constitutional copy number variants: A ClinGen/ACMG joint consensus recommendation

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