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

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. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p<0.001). For MGPs, the rate was positively correlated with the total number of genes. The use of trios (patient with parental samples) in ES/GS reduced the inconclusive report rate (18.9% vs 27.6%; p<0.001). The reduced rate of VUS in ES/GS testing compared to MGPs is best explained by current laboratory reporting practices of comprehensive VUS reporting for MGPs in contrast to clinical correlation and strength of pathogenicity evidence to inform which VUS are reported in ES/GS. We recommend changes in current practices to reduce the burden of VUS on providers and patients. ### Competing Interest Statement All authors are employed by clinical laboratories offering genetic testing services, as indicated by their affiliations. Additional conflicts include: Swaroop Aradhya, Elaine Chen, Kathryn E Hatchell, and Dianalee McKnight - Stockholders of Invitae; Christina DiVincenzo, Izabela D Karbassi - Stockholders of Quest Diagnostics; Kyle Retterer - Stockholder of Sema4 and Opko Health; Kyle W Davis, Nir Neerman, and Christine Stanley - Stockholders of Variantyx ### Funding Statement HR's participation in this study was funded in part by the National Human Genome Research Institute under award U24HG006834. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NOT HUMAN SUBJECT RESEARCH DETERMINATION Date: September 21, 2022 Title of Project: Comparing the rate of uncertainty generated from panels versus genomic sequencing tests Project Lead Name: Heidi Rehm The above referenced project does not meet the criteria for human subject research as defined by Mass General Brigham Human Research Office policies and Health and Human Services regulations set forth in 45 CFR 46. Based on the information you provided this activity is not human subjects research because does not involve human subjects. The project does not require IRB approval. This NHSR activity is not applicable for [Clinicaltrials.gov][1] registration. Please retain a copy of this letter in your project file. Please feel free to contact our office directly (partnersirb{at}partners.org) with any questions related to this determination. Sincerely, Ben McGill, MS, CIP Expedited Specialist II, Human Research Affairs bmcgill1{at}partners.org I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All aggregate data produced in the present study are available upon reasonable request to the authors [1]: http://Clinicaltrials.gov