The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

• DOI: 10.1016/j.gim.2023.100947
• Publication Date: 2023-07-30T13:52:58Z
• Authors: Heidi L. Rehm; Joseph T. Alaimo; Swaroop Aradhya; Pinar Bayrak-Toyd...; Hunter Best; Rhonda Brandon; Jillian G. Buchan; Elizabeth C. Chao; Elaine Chen; Jacob Clifford; Ana S.A. Cohen; Laura K. Conlin; Soma Das; Kyle W. Davis; Daniela del Gaudio; Florencia Del Viso; Christina DiVincenzo; Marcia Eisenberg; Lucia Guidugli; Monia B. Hammer; Steven M. Harrison; Kathryn E. Hatchell; Lindsay Havens Dyer; Lily U. Hoang; James M. Holt; Vaidehi Jobanputra; Izabela D. Karbassi; Hutton M. Kearney; Melissa A. Kelly; Jacob M. Kelly; Michelle L. Kluge; Timothy Komala; Paul Kruszka; Lynette Lau; Matthew S. Lebo; Christian R. Mars...; Dianalee McKnight; Kirsty McWalter; Yan Meng; Narasimhan Nagan; Christian S. Neck...; Nir Neerman; Zhiyv Niu; Vitoria K. Paolillo; Sarah A. Paolucci; Denise Perry; Tina Pesaran; Kelly Radtke; Kristen J. Rasmussen; Kyle Retterer; Carol J. Saunders; Elizabeth Spiteri; Christine Stanley; Anna Szuto; Ryan J. Taft; Isabelle Thiffault; Brittany C. Thomas; Amanda Thomas-Wilson; Erin Thorpe; Timothy J. Tidwell; Meghan C. Towne; Hana Zouk; Christian Marshall; Linyan Meng; Vaidehi Jobanputra; Ryan Taft; Euan Ashley; Ghunwa Nakouzi; Wei Shen; Stephen Kingsmore; Heidi Rehm
• Keywords: Exome

AbstractPURPOSEVariants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.METHODSRates of inconclusive results due to VUS were collected from over 1.5 million sequencing test results from 19 clinical laboratories in North America from 2020 - 2021.RESULTSWe found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared to MGPs (32.6%; p<0.0001). For MGPs, the rate of inconclusive results correlated with panel size. The use of trios reduced inconclusive rates (18.9% vs 27.6%; p<0.001) whereas the use of GS compared to ES had no impact (22.2% vs 22.6%; p=ns).CONCLUSIONThe high rate of VUS observed in diagnostic MGP testing warrants examining current variant reporting practices. We propose several approaches to reduce reported VUS rates, while directing clinician resources towards important VUS follow-up.