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. 2022 Feb;24(2):454-462.
doi: 10.1016/j.gim.2021.10.010. Epub 2021 Nov 30.

Reanalysis of eMERGE phase III sequence variants in 10,500 participants and infrastructure to support the automated return of knowledge updates

Hana Zouk  1 , Wanfeng Yu  2 , Andrea Oza  2 , Megan Hawley  2 , Prathik K Vijay Kumar  2 , Christopher Koch  2 , Lisa M Mahanta  2 , John B Harley  3 , Gail P Jarvik  4 , Elizabeth W Karlson  5 , Kathleen A Leppig  6 , Melanie F Myers  7 , Cynthia A Prows  8 , Marc S Williams  9 , Scott T Weiss  5 , Matthew S Lebo  10 , Heidi L Rehm  11
Affiliations

Reanalysis of eMERGE phase III sequence variants in 10,500 participants and infrastructure to support the automated return of knowledge updates

Hana Zouk et al. Genet Med. 2022 Feb.

Abstract

Purpose: The clinical genomics knowledgebase is dynamic with variant classifications changing as newly identified cases, additional population data, and other evidence become available. This is a challenge for the clinical laboratory because of limited resource availability for variant reassessment.

Methods: Throughout the Electronic Medical Records and Genomics phase III program, clinical sites associated with the Mass General Brigham/Broad sequencing center received automated, real-time notifications when reported variants were reclassified. In this study, we summarized the nature of these reclassifications and described the proactive reassessment framework we used for the Electronic Medical Records and Genomics program data set to identify variants most likely to undergo reclassification.

Results: Reanalysis of 1855 variants led to the reclassification of 2% (n = 45) of variants, affecting 0.6% (n = 67) of participants. Of these reclassifications, 78% (n = 35) were high-impact changes affecting reportability, with 8 variants downgraded from likely pathogenic/pathogenic to variants of uncertain significance (VUS) and 27 variants upgraded from VUS to likely pathogenic/pathogenic. Most upgraded variants (67%) were initially classified as VUS-Favor Pathogenic, highlighting the benefit of VUS subcategorization. The most common reason for reclassification was new published case data and/or functional evidence.

Conclusion: Our results highlight the importance of periodic sequence variant reevaluation and the need for automated approaches to advance routine implementation of variant reevaluations in clinical practice.

Keywords: Automated variant reclassification alerts; Variant reassessment framework; Variant reclassification; eMERGE.

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Conflict of interest statement

Conflict of Interest H.Z., W.Y., A.O., M.H., P.K.V.K., C.K., L.M.M., E.W.K., S.T.W., M.S.L., and H.L.R. were either employed at Mass General Brigham at the time this work was performed or are current employees of Mass General Brigham, which receives royalties on the sale of GeneInsight Software. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Outcome of variants identified for reassessment.
Three concurrent strategies to identify and prioritize variants for reassessment were applied on variants identified post-filtration in the eMERGE III dataset from our SC. These include: analysis using ClinVar, predicted loss of function (pLOF) reanalysis, and querying all unreported eMERGE variants (VUS or below) against LMM’s current knowledgebase (grey boxes). Site triggered requests and auto-updated variants are also noted here. The number of variants identified using each approach are noted in orange boxes, variants prioritized for reassessment are noted in the blue boxes, the outcome of reassessments is noted in the green boxes and the final summary of total variants are noted at the bottom in green as well. Of note, two pLOF variants and one site requested variant were also flagged for reclassification by the ClinVar-driven reassessment.
Figure 2.
Figure 2.. Original subclassification of the 28 VUSs upgraded after reassessment.
The proportion of upgraded variants that were initially classified as variants of uncertain significance (VUS) or VUS-Favor Pathogenic (VUS-FP) are depicted. No variants initially classified as VUS-Favor Benign (VUS-FB) were upgraded in classification. Additionally, the different types of evidence criteria leading to these upgrades are shown. The vast majority of the initial VUS-FP required only one additional type of evidence for reclassification, whereas VUSs required two different types of evidence or a higher strength of one evidence type to be upgraded to LP/P.
Figure 3 -
Figure 3 -. Breakdown of reclassified variants
A. Classification changes across 45 reassessed variants. Reclassification resulted in upgrading a likely pathogenic (LP) variant to pathogenic (P) or a variant of uncertain significance (VUS) to LP/P, or in downgrading a previously classified P/ LP variant to a VUS. The number of variants belonging to each category is shown in the bar graph. High-impact reclassifications affecting variant reportability are indicated inside the box. B. Reasons for reclassifications. Variants were reviewed to identify factors that led to their reclassification, depicted here.
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