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. 2023 Dec;25(12):100947.
doi: 10.1016/j.gim.2023.100947. Epub 2023 Jul 30.

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

Heidi L Rehm  1 , Joseph T Alaimo  2 , Swaroop Aradhya  3 , Pinar Bayrak-Toydemir  4 , Hunter Best  4 , Rhonda Brandon  5 , Jillian G Buchan  6 , Elizabeth C Chao  7 , Elaine Chen  8 , Jacob Clifford  7 , Ana S A Cohen  2 , Laura K Conlin  9 , Soma Das  10 , Kyle W Davis  11 , Daniela Del Gaudio  10 , Florencia Del Viso  12 , Christina DiVincenzo  13 , Marcia Eisenberg  14 , Lucia Guidugli  15 , Monia B Hammer  15 , Steven M Harrison  7 , Kathryn E Hatchell  8 , Lindsay Havens Dyer  5 , Lily U Hoang  7 , James M Holt  16 , Vaidehi Jobanputra  17 , Izabela D Karbassi  13 , Hutton M Kearney  18 , Melissa A Kelly  16 , Jacob M Kelly  16 , Michelle L Kluge  18 , Timothy Komala  7 , Paul Kruszka  5 , Lynette Lau  19 , Matthew S Lebo  20 , Christian R Marshall  21 , Dianalee McKnight  8 , Kirsty McWalter  5 , Yan Meng  22 , Narasimhan Nagan  23 , Christian S Neckelmann  22 , Nir Neerman  11 , Zhiyv Niu  18 , Vitoria K Paolillo  12 , Sarah A Paolucci  6 , Denise Perry  24 , Tina Pesaran  7 , Kelly Radtke  7 , Kristen J Rasmussen  18 , Kyle Retterer  5 , Carol J Saunders  25 , Elizabeth Spiteri  26 , Christine Stanley  11 , Anna Szuto  27 , Ryan J Taft  24 , Isabelle Thiffault  2 , Brittany C Thomas  24 , Amanda Thomas-Wilson  28 , Erin Thorpe  24 , Timothy J Tidwell  29 , Meghan C Towne  7 , Hana Zouk  20 ; Medical Genome Initiative Steering Committee
Collaborators, Affiliations

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

Heidi L Rehm et al. Genet Med. 2023 Dec.

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 to 2021.

Results: We found a lower rate of inconclusive test results due to VUSs from ES/GS (22.5%) compared with MGPs (32.6%; P < .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 < .0001), whereas the use of GS compared with 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 toward important VUS follow-up.

Keywords: Laboratory reporting methods; Multi-gene panels; VUS; Variants of uncertain significance.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest All authors are or were employed by clinical laboratories offering genetic testing services, as indicated by their affiliations. Additional existing conflicts or those that were relevant at the time of data collection and publication include the following: Swaroop Aradhya, Elaine Chen, Kathryn E. Hatchell, and Dianalee McKnight - stockholders of Invitae Corp.; Christina DiVincenzo, Izabela D. Karbassi - stockholders of Quest Diagnostics; Kyle Retterer - past stockholder of Sema4 and Opko Health; Kyle W. Davis, Nir Neerman, and Christine Stanley - stockholders of Variantyx; Denise Perry, Ryan Taft, Erin Thorpe, and Brittany Thomas - stockholders of Illumina, Inc.

Figures

Figure 1.
Figure 1.. Comparison of Rates of Inconclusive Results due to VUS by Multi-Gene Panel versus ES/GS Testing.
Panel A shows a statistically significant reduction in inconclusive rates due to VUS in ES/GS sequencing compared to panels. Panel B shows a breakdown in rates by panel size. Panel C shows test volume for each bin.
Figure 2.
Figure 2.. Rate of Inconclusive Results due to VUS by Test Type and Disease Area.
Rates generally correlate with multi-gene panel size. Use of genomic testing with trio analysis when available, reduces VUS rate escalation seen with panel size increases. Note: ES/GS results are plotted according to corresponding panel size for the same disease area but actual number of genes analyzed are not captured per ES/GS test. Disease areas (except “not specified”) are labeled when both panel and ES/GS data were available. Open circles represent disease areas with no corresponding ES/GS data. For detailed data for all disease areas, see supplemental Table 3. Supplemental Table 4 includes trio rates for each disease area with comparable data.
Figure 3.
Figure 3.. Testing Results Broken down by VUS Sub-tier and Test Type.
Two laboratories (Quest and Mass General Brigham) use VUS sub-tiers and these data show the breakdown of VUS reported in MGP and ES/GS testing.
See this image and copyright information in PMC

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