Copy number variants in the ACMG secondary finding genes: A reporting framework for clinical cytogeneticists

Purpose To determine the pathogenicity and frequency of copy number variants (CNV) in the 81 secondary finding (SFv3.2) genes recommended by the American College of Medical Genetics and Genomics (ACMG). Methods Review of published evidence on pathogenicity of partial or complete copy number losses or gains in ACMG SFv3.2 was performed. Frequency of reportable CNVs in the ACMG SFv3.2 genes was investigated among 10,959 patients tested by chromosomal microarray analysis (CMA) in a single academic testing laboratory at the University of Pittsburgh Medical Center (UPMC) during 2011-2023. Results We identified 57 ACMG SFv3.2 genes for which sufficient evidence supports reporting of partial or complete copy number losses as secondary findings. On the contrary, reporting of copy number gains was not supported by evidence in any of the ACMG SFv3.2 genes. Overall, CNVs in SFv3.2 genes were detected in 32/10,959 (0.29% or 1 in 343) patients in our cohort. Conclusion This study provides a framework for consistent reporting of CNVs, detected by CMA, exome, or genome sequencing, in any of the ACMG SFv3.2 genes. To our knowledge, this is the largest cohort of patients studied for estimation of frequency of reportable CNVs in the ACMG SFv3.2 genes.