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

基因 遗传学 计算生物学 生物
作者
Heidi L. Rehm,Joseph T. Alaimo,Swaroop Aradhya,Pinar Bayrak‐Toydemir,Hunter Best,Rhonda Brandon,Jillian G. Buchan,Elizabeth Chao,Elaine Chen,Jacob Clifford,Ana S.A. Cohen,Laura K. Conlin,Soma Das,Kyle Davis,Daniela del Gaudio,Florencia del Viso,Christina DiVincenzo,Marcia Eisenberg,Lucia Guidugli,Monia Hammer,Steven M. Harrison,Kathryn E. Hatchell,Lindsay Havens Dyer,Lily Hoang,James Holt,Vaidehi Jobanputra,Izabela Karbassi,Hutton M. Kearney,Melissa Kelly,Jacob L. McCauley,Michelle L. Kluge,Timothy Komala,Paul Kruszka,Lynette Lau,Matthew S. Lebo,Christian R. Marshall,Dianalee McKnight,Kirsty McWalter,Yan Meng,Narasimhan Nagan,Christian S Neckelmann,Nir Neerman,Zhiyv Niu,Vitoria K Paolillo,Sarah A Paolucci,Denise Perry,Tina Pesaran,Kelly Radtke,Kristen Rasmussen,Kyle Retterer,Carol Saunders,Elizabeth Spiteri,Christine M. Stanley,Anna Szuto,Ryan J. Taft,Isabelle Thiffault,Brittany C. Thomas,Amanda Thomas‐Wilson,Erin Thorpe,Timothy Tidwell,Meghan C. Towne,Hana Zouk
出处
期刊:Cold Spring Harbor Laboratory - medRxiv 被引量:2
标识
DOI:10.1101/2022.09.21.22279949
摘要

Abstract PURPOSE Variants 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. METHODS Rates 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. RESULTS We 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). CONCLUSION The 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.
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