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

被引：63

作者：

Rehm, Heidi L. ^{[1
,2
,3
,34
]}

Alaimo, Joseph T. ^{[4
,5
,6
]}

Aradhya, Swaroop ^{[7
,8
]}

Bayrak-Toydemir, Pinar ^{[9
,10
]}

Best, Hunter ^{[9
,10
]}

Brandon, Rhonda ^{[11
]}

Buchan, Jillian G. ^{[12
]}

Chao, Elizabeth C. ^{[13
]}

Chen, Elaine ^{[7
]}

Clifford, Jacob ^{[13
]}

Cohen, Ana S. A. ^{[4
,5
,6
]}

Conlin, Laura K. ^{[14
,15
]}

Das, Soma ^{[16
]}

Davis, Kyle W. ^{[17
]}

del Gaudio, Daniela ^{[16
]}

Del Viso, Florencia ^{[4
]}

Divincenzo, Christina ^{[18
]}

Eisenberg, Marcia ^{[19
]}

Guidugli, Lucia ^{[20
]}

Hammer, Monia B. ^{[20
]}

Harrison, Steven M. ^{[13
]}

Hatchell, Kathryn E. ^{[7
]}

Dyer, Lindsay Havens ^{[11
]}

Hoang, Lily U. ^{[13
]}

Holt, James M. ^{[21
]}

Jobanputra, Vaidehi ^{[22
,23
]}

Karbassi, Izabela D. ^{[18
]}

Kearney, Hutton M. ^{[24
]}

Kelly, Melissa A. ^{[21
]}

Kelly, Jacob M. ^{[21
]}

Kluge, Michelle L. ^{[24
]}

Komala, Timothy

Kruszka, Paul ^{[11
]}

Lau, Lynette ^{[25
]}

Lebo, Matthew S. ^{[3
,26
]}

Marshall, Christian R. ^{[25
,27
]}

Mcknight, Dianalee ^{[7
]}

Mcwalter, Kirsty ^{[11
]}

Meng, Yan ^{[28
]}

Nagan, Narasimhan ^{[29
]}

Neckelmann, Christian S. ^{[28
]}

Neerman, Nir ^{[17
]}

Niu, Zhiyv ^{[24
]}

Paolillo, Vitoria K. ^{[4
]}

Paolucci, Sarah A. ^{[12
]}

Perry, Denise ^{[30
]}

Pesaran, Tina

Radtke, Kelly ^{[11
,13
]}

Rasmussen, Kristen J.

Retterer, Kyle

机构：

[1] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA

[2] Broad Inst MIT & Harvard, Med & Populat Genet, Cambridge, MA USA

[3] Harvard Med Sch, Pathol, Boston, MA USA

[4] Childrens Mercy Hosp, Dept Pathol & Lab Med, Kansas City, MO USA

[5] Univ Missouri, Sch Med, Dept Pediat, Kansas City, MO USA

[6] Childrens Mercy Hosp, Genom Med Ctr, Kansas City, MO USA

[7] Invitae, San Francisco, CA USA

[8] Stanford Univ, Sch Med, Dept Pathol, Palo Alto, CA USA

[9] ARUP Labs, Salt Lake City, UT USA

[10] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA

[11] GeneDx LLC, Gaithersburg, MD USA

[12] Univ Washington, Genet Div, Lab Med & Pathol, Seattle, WA USA

[13] Ambry Genet, Aliso Viejo, CA USA

[14] Childrens Hosp Philadelphia, Div Genom Diagnost, Philadelphia, PA USA

[15] Univ Penn, Pathol & Lab Med, Philadelphia, PA USA

[16] Univ Chicago, Human Genet, Chicago, IL USA

[17] Variantyx, Framingham, MA USA

[18] Quest Diagnost, Marlborough, MA USA

[19] Labcorp, Womens Hlth & Genet, Res Triangle Pk, NC USA

[20] Rady Childrens Inst Genom Med, San Diego, CA USA

[21] HudsonAlpha Clin Serv Lab LLC, Huntsville, AL USA

[22] New York Genome Ctr, Mol Diagnost, New York, NY USA

[23] Columbia Univ, Irving Med Ctr, Dept Pathol & Cell Biol, New York, NY USA

[24] Mayo Clin, Dept Lab Med & Pathol, Div Lab Genet & Genom, Rochester, MN USA

[25] Hosp Sick Children, Dept Paediat Lab Med, Div Genome Diagnost, Toronto, ON, Canada

[26] Mass Gen Brigham, Lab Mol Med, Cambridge, MA USA

[27] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[28] Fulgent Genet, Temple City, CA USA

[29] Labcorp, Womens Hlth & Genet, Westborough, MA USA

[30] Illumina Inc, San Diego, CA USA

[31] Univ Missouri, Sch Med, Dept Pediat & Pathol, Kansas City, MO USA

[32] Stanford Med, Dept Pathol, Palo Alto, CA USA

[33] Hosp Sick Children, Clin & Metab Genet, Toronto, ON, Canada

[34] Massachusetts Gen Hosp, Ctr Genom Med, Simches Res Bldg, CPZN 5 812, 185 Cambridge St, Boston, MA 02114 USA

来源：

GENETICS IN MEDICINE | 2023年 / 25卷 / 12期

关键词：

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

D O I：

10.1016/j.gim.2023.100947

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. (c) 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

引用

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