Abstract
Exome sequencing is an innovative next-generation sequencing technology that examines the majority of disease-causing genes with a single test. Physicians and patients resort to exome sequencing to probe for a genetic cause of disease. The technology produces about 20,000 variants and many are of uncertain clinical relevance. Drawing from ethnographic field notes and audio recordings of over 1,500 patient cases discussed at genetic data board meetings over a three-year period, this article reports on how a collective of laboratory scientists and clinicians contend practically and conceptually with variants of uncertain significance (VUS). Rather than standardizing the inclusion criteria for a VUS, the collective contextualizes each VUS with its own evidentiary narrative. The VUS then becomes subject to revision based on evolving evidence, further testing, and updated interpretations. We argue that the epistemic uncertainty of VUS becomes productive; it indicates future causality and suggests that genetic causes can explain patients’ symptoms even if no known pathogenic variants could be located.
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Notes
Geneticists use VUS both in singular and plural as a noun and a verb and sound it out as the three letters, except for one company, where employees speak about “VOUS” for Variant Of Uncertain Significance, and “VOUSES.”
Genetic testing also requires accreditation by the College of American Pathologists or the Joint Commission. The Food and Drug Administration has also begun to consider regulating genetic tests.
The exome team’s informed consent form did not allow for informing relatives at that time. Also, not all ATM mutations are necessarily actionable.
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Acknowledgements
The authors thank Ruth Baxter, Tanya Stivers, the reviewers, editors, and members of the UCLA Medical Sociology working group for helpful comments. The manuscript consists of original material not under review elsewhere. The research received IRB approval. The research was funded by an NSF Grant (SES-1256874). The authors do not have a financial interest in the research presented.
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Timmermans, S., Tietbohl, C. & Skaperdas, E. Narrating uncertainty: Variants of uncertain significance (VUS) in clinical exome sequencing. BioSocieties 12, 439–458 (2017). https://doi.org/10.1057/s41292-016-0020-5
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DOI: https://doi.org/10.1057/s41292-016-0020-5