Utility and Outcomes of the 2019 American College of Medical Genetics and Genomics–Clinical Genome Resource Guidelines for Interpretation of Copy Number Variants with Borderline Classifications at an Academic Clinical Diagnostic Laboratory

Andy Drackley, Casey Brew, Alissa Wlodaver, Sara Spencer, Katrin Leuer, Pamela Rathbun, Joel Charrow, Xuwen Wieneke, Kai Lee Yap*, Alexander Ing

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

In 2019, the American College of Medical Genetics and Genomics and the Clinical Genome Resource published updated technical standards for the interpretation and reporting of copy number variants (CNVs), introducing a semiquantitative classification system to improve standardization and consistency between laboratories. Evaluation of these guidelines' performance will inform laboratories about the impact of their implementation into clinical practice. A total of 145 difficult-to-classify CNVs, originally assessed by an academic molecular diagnostic laboratory, were re-interpreted/classified according to the American College of Medical Genetics and Genomics–Clinical Genome Resource guidelines. Classifications between interpretation systems were then compared. The concordance rate was 60.7%, and significantly more variants of uncertain significance 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 variant of uncertain significance rate was largely due to laboratory-specific practices for variant interpretation and reporting and differences in utilization of general population data. Laboratory-specific policies and practices may need to be addressed for true standardization. Challenges to consistent guideline 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 to further improve classification standardization.

Original languageEnglish (US)
Pages (from-to)1100-1111
Number of pages12
JournalJournal of Molecular Diagnostics
Volume24
Issue number10
DOIs
StatePublished - Oct 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'Utility and Outcomes of the 2019 American College of Medical Genetics and Genomics–Clinical Genome Resource Guidelines for Interpretation of Copy Number Variants with Borderline Classifications at an Academic Clinical Diagnostic Laboratory'. Together they form a unique fingerprint.

Cite this