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A framework for the evaluation and reporting of incidental findings in clinical genomic testing

European Journal of Human Genetics (2024)Cite this article

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Abstract

Currently, there are no widely accepted recommendations in the genomics field guiding the return of incidental findings (IFs), defined here as unexpected results that are unrelated to the indication for testing. Consequently, reporting policies for IFs among laboratories offering genomic testing are variable and may lack transparency. Herein we describe a framework developed to guide the evaluation and return of IFs encountered in probands undergoing clinical genome sequencing (cGS). The framework prioritizes clinical significance and actionability of IFs and follows a stepwise approach with stopping points at which IFs may be recommended for return or not. Over 18 months, implementation of the framework in a clinical laboratory facilitated the return of actionable IFs in 37 of 720 (5.1%) individuals referred for cGS, which is reduced to 3.1% if glucose-6-phosphate dehydrogenase (G6PD) deficiency is excluded. This framework can serve as a model to standardize reporting of IFs identified during genomic testing.

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Fig. 1: Evaluating clinical significance of potential IFs by variant type.
Fig. 2: Assessing the actionability of clinically significant IFs.

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Data availability

Gene–disease validity classifications are available through ClinGen [19] and/or the GenCC [20]. Variant classifications are available through ClinVar [39]. Actionability curations are available through ClinGen [19]. Further information and requests should be directed to and will be fulfilled by the lead contact, CMB (carolynm.brown26@illumina.com) or senior author AJC (acoffey@illumina.com).

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Acknowledgements

We thank the ILS interpretation and reporting team: Krista Bluske, Maren Bennett, CMB, Matthew P. Brown, Amanda Buchanan, Brendan Burns, Nicole J. Burns, AC, Aditi Chawla, Amanda R. Clause, AJC, Katie Golden-Grant, Alka Malhotra, Becky Milewski, Samin A. Sajan, Zinayida Schlachetzki, Sarah Schmidt, Revathi Rajkumar, Julie P. Taylor, and Brittany Thomas. We thank Brittany Thomas for thoughtful review.

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No specific funding.

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Author notes

  1. These authors contributed equally: Laura M. Amendola, Anjana Chandrasekhar.

Authors and Affiliations

  1. Medical Genomics Research, Illumina, Inc., San Diego, CA, 92122, USA

    Carolyn M. Brown, Laura M. Amendola, Anjana Chandrasekhar, Akanchha Kesari, Erin Thorpe, Denise L. Perry, Ryan J. Taft & Alison J. Coffey

  2. Oncology, Natera Inc., Austin, TX, 78753, USA

    R. Tanner Hagelstrom

  3. Scripps MD Anderson Cancer Center, San Diego, CA, 92121, USA

    Gillian Halter

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Contributions

Conceptualization: LMA, CMB, AC, AJC, AK, RTH, ET. Data curation: LMA, CMB, AC, AJC. Formal Analysis: LMA, CMB, AC, AJC. Investigation: LMA, CMB, AC, AJC, GH, ISL interpretation and reporting team. Supervision: AJC, RTH, AK, DLP, RJT. Visualization: CMB, AC. Writing – original draft: LMA, CMB, AC, AJC. Writing – review & editing: LMA, CMB, AC, AJC, DLP, RJT, ET.

Corresponding authors

Correspondence to Carolyn M. Brown or Alison J. Coffey.

Ethics declarations

Competing interests

All authors are shareholders of Illumina Inc. All authors are employees of Illumina Inc., except for GH and RTH who are former employees of Illumina Inc.

Ethical approval

Data analysis was completed under an institutional review board research exemption (ID Number: ICSL-001). Informed consent was not required since no human subjects were enrolled; all study samples were de-identified residual specimens left over from routine clinical care.

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Supplementary information

Title: iHope collaborator incidental findings survey

41431_2024_1575_MOESM2_ESM.pdf

Supplementary figure 1 title: Select responses from the “iHope collaborator incidental findings survey”, which examined physician and genetic counselor attitudes surrounding IFs in clinical genomic tes

41431_2024_1575_MOESM3_ESM.docx

Supplementary figure 1 title: Select responses from the “iHope collaborator incidental findings survey”, which examined physician and genetic counselor attitudes surrounding IFs in clinical genomic tes

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Brown, C.M., Amendola, L.M., Chandrasekhar, A. et al. A framework for the evaluation and reporting of incidental findings in clinical genomic testing. Eur J Hum Genet (2024). https://doi.org/10.1038/s41431-024-01575-1

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