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

Medical Genome Initiative Steering Committee

doi:10.1016/j.gim.2023.100947

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

Medical Genome Initiative Steering Committee

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	100947
Journal	Genetics in Medicine
Volume	25
Issue number	12
DOIs	https://doi.org/10.1016/j.gim.2023.100947
State	Published - Dec 2023

Keywords

Laboratory reporting methods
Multi-gene panels
VUS
Variants of uncertain significance

ASJC Scopus subject areas

Genetics(clinical)

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10.1016/j.gim.2023.100947

Cite this

@article{28c0492b70f44e6d8f4e2db97c792ff4,

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

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",

author = "{Medical Genome Initiative Steering Committee} and Rehm, {Heidi L.} and Alaimo, {Joseph T.} and Swaroop Aradhya and Pinar Bayrak-Toydemir and Hunter Best and Rhonda Brandon and Buchan, {Jillian G.} and Chao, {Elizabeth C.} and Elaine Chen and Jacob Clifford and Cohen, {Ana S.A.} and Conlin, {Laura K.} and Soma Das and Davis, {Kyle W.} and {del Gaudio}, Daniela and {Del Viso}, Florencia and Christina DiVincenzo and Marcia Eisenberg and Lucia Guidugli and Hammer, {Monia B.} and Harrison, {Steven M.} and Hatchell, {Kathryn E.} and Dyer, {Lindsay Havens} and Hoang, {Lily U.} and Holt, {James M.} and Vaidehi Jobanputra and Karbassi, {Izabela D.} and Kearney, {Hutton M.} and Kelly, {Melissa A.} and Kelly, {Jacob M.} and Kluge, {Michelle L.} and Timothy Komala and Paul Kruszka and Lynette Lau and Lebo, {Matthew S.} and Marshall, {Christian R.} and Dianalee McKnight and Kirsty McWalter and Yan Meng and Narasimhan Nagan and Neckelmann, {Christian S.} and Nir Neerman and Zhiyv Niu and Paolillo, {Vitoria K.} and Paolucci, {Sarah A.} and Denise Perry and Tina Pesaran and Kelly Radtke and Rasmussen, {Kristen J.} and Kyle Retterer",

note = "Publisher Copyright: {\textcopyright} 2023 American College of Medical Genetics and Genomics",

year = "2023",

month = dec,

doi = "10.1016/j.gim.2023.100947",

language = "English (US)",

volume = "25",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Lippincott Williams and Wilkins",

number = "12",

}

TY - JOUR

T1 - The landscape of reported VUS in multi-gene panel and genomic testing

T2 - Time for a change

AU - Medical Genome Initiative Steering Committee

AU - Rehm, Heidi L.

AU - Alaimo, Joseph T.

AU - Aradhya, Swaroop

AU - Bayrak-Toydemir, Pinar

AU - Best, Hunter

AU - Brandon, Rhonda

AU - Buchan, Jillian G.

AU - Chao, Elizabeth C.

AU - Chen, Elaine

AU - Clifford, Jacob

AU - Cohen, Ana S.A.

AU - Conlin, Laura K.

AU - Das, Soma

AU - Davis, Kyle W.

AU - del Gaudio, Daniela

AU - Del Viso, Florencia

AU - DiVincenzo, Christina

AU - Eisenberg, Marcia

AU - Guidugli, Lucia

AU - Hammer, Monia B.

AU - Harrison, Steven M.

AU - Hatchell, Kathryn E.

AU - Dyer, Lindsay Havens

AU - Hoang, Lily U.

AU - Holt, James M.

AU - Jobanputra, Vaidehi

AU - Karbassi, Izabela D.

AU - Kearney, Hutton M.

AU - Kelly, Melissa A.

AU - Kelly, Jacob M.

AU - Kluge, Michelle L.

AU - Komala, Timothy

AU - Kruszka, Paul

AU - Lau, Lynette

AU - Lebo, Matthew S.

AU - Marshall, Christian R.

AU - McKnight, Dianalee

AU - McWalter, Kirsty

AU - Meng, Yan

AU - Nagan, Narasimhan

AU - Neckelmann, Christian S.

AU - Neerman, Nir

AU - Niu, Zhiyv

AU - Paolillo, Vitoria K.

AU - Paolucci, Sarah A.

AU - Perry, Denise

AU - Pesaran, Tina

AU - Radtke, Kelly

AU - Rasmussen, Kristen J.

AU - Retterer, Kyle

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Laboratory reporting methods

KW - Multi-gene panels

KW - VUS

KW - Variants of uncertain significance

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UR - http://www.scopus.com/inward/citedby.url?scp=85173250792&partnerID=8YFLogxK

U2 - 10.1016/j.gim.2023.100947

DO - 10.1016/j.gim.2023.100947

M3 - Article

C2 - 37534744

AN - SCOPUS:85173250792

SN - 1098-3600

VL - 25

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 12

M1 - 100947

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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