Utility and Outcomes of the 2019 ACMG-ClinGen Guidelines for Interpretation of Copy-Number Variants With Borderline Classifications at an Academic Clinical Diagnostic Laboratory.

In 2019, ACMG and the Clinical Genome Resource (ClinGen) published updated technical standards for the interpretation and reporting of copy-number variants (CNVs), introducing a semi-quantitative classification system which aims to foster greater standardization and consistency between laboratories. Evaluation of these guidelines' performance will inform laboratories about the impact of their implementation into clinical practice. 145 difficult-to-classify CNVs originally assessed by an academic molecular diagnostic laboratory were re-interpreted/classified according to the ACMG-ClinGen guidelines. Classifications between interpretation systems were then compared. The concordance rate was 60.7%, and significantly more variants of uncertain significance (VUS) were obtained when using the guidelines (n=98) versus the laboratory's classification system (n=49) (p<0.001). The concordance rate was presumably impacted by the intentionally unclear nature of the selected variants. The difference in VUS rate was largely due to laboratory-specific practices for variant interpretation and reporting, as well as differences in utilization of general population data. Laboratory-specific policies and practices may need to be addressed for true standardization to be achieved. Challenges to consistent guidelines utilization are centered around the general lack of high-quality curated data available for CNV interpretations and the inherent subjectivity in the selection of evidence criteria and application of evidence points. Multiple aspects of the guidelines were highlighted as potential opportunities for subsequent refinements to further improve classification standardization.