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ACMG, ClinGen Publish Recommendations for Interpretation, Reporting of CNVs

NEW YORK – The American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) have released new joint consensus recommendations to help guide the evaluation of constitutional copy number variants (CNVs) in a consistent way across clinical laboratories.

The recommendations, which were recently published in Genetics in Medicine, update the existing ACMG clinical laboratory practice standards for evaluating CNVs. The researchers in the joint working group are recommending that copy number analysis be used as a first-tier approach for the evaluation of individuals with neurodevelopmental disorders, such as intellectual disability, developmental delay and autism spectrum disorder, as well as for individuals with multiple congenital anomalies and for fetuses with ultrasound abnormalities.

"It is our hope that having standards that are widely available, up to date, and flexible enough to incorporate lessons learned from the ever-evolving clinical genomics knowledge base will help to reduce discordance in clinical classifications and will improve clinical care," Christa Lese Martin, a researcher at the Autism & Developmental Medicine Institute and the paper's senior author, said in a statement.

The new report is an update from previous recommendations published in 2011 entitled "American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants," and is intended to complement a 2015 paper entitled "Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology."

The researchers are now recommending that labs use the same five-tier system used in sequence variant classification: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. This would replace the previous standards, which recommended utilizing "likely pathogenic" and "likely benign" as sub-categories under "uncertain significance," they wrote.

They also encouraged labs to uncouple the classification of the variant from the clinical significance for the patient, noting that patient phenotype may be an important piece of evidence to consider when determining variant classification but that it should not override other evidence for or against the pathogenicity of the variant.

Further, the working group developed points-based scoring metrics to systematically guide labs through the classification of copy number losses and gains. In this scoring system, the various types of evidence considered when evaluating CNVs are awarded points based on their relative strengths — evidence of pathogenicity is awarded positive point values while evidence against pathogenicity is awarded negative point values. The sum of all accumulated points would then lead to a suggested classification.

"The scoring metrics are intended to be a guide to provide more structure and transparency to the CNV evaluation," Erin Rooney Riggs, Autism & Developmental Medicine Institute researcher and the paper's lead author, said in a statement. "We have developed this type of quantitative metric for other types of curation within ClinGen which are being used successfully to increase consistency in data interpretation."

The authors also noted that no single formula or algorithm for CNV interpretation would substitute for adequate training in genetics and good clinical judgment, and further recommended that clinical reporting of constitutional CNVs be performed by individuals with appropriate training and certification, preferably in labs that include both cytogenetic and molecular genetic expertise.

"Systematic approaches to variant interpretation (such as this one) will evolve over time, particularly as knowledge regarding the relationships between genomic variation and human health improve," the authors concluded. "Groups are encouraged to use this framework as a guide, always using professional judgment when opting to incorporate emerging knowledge, methods, and resources, and documenting the process by which this evidence is used to arrive at a variant classification."