Narrating uncertainty: Variants of uncertain significance (VUS) in clinical exome sequencing
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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.
Keywordsuncertainty bioclinical collective standardization narrative exome sequencing next-generation sequencing genetic testing laboratory
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.
- Abbott, A. (1988) The System of Professions. Chicago: The University of Chicago Press.Google Scholar
- Duster, T. (1990) Backdoor to Eugenics. New York: Routledge.Google Scholar
- Eggington, J.M., Bowles, K.R., Moyes, K., Manley, S., Esterling, L., Sizemore, S., Rosenthal, E., Theisen, A., Saam, J., Arnell, C., Pruss, D., Bennett, J., Burbidge, L.A., Roa, B. and Wenstrup, R.J. (2014) A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clinical Genetics 86: 229–237.CrossRefGoogle Scholar
- Green, R.C., Berg, J.S., Grody, W.W., Kalia, S.S., Korf, B.R., Martin, C.L., Mcguire, A.L., Nussbaum, R.L., O’daniel, J.M., Ormond, K.E., Rehm, H.L., Watson, M.S., Williams, M.S. and Biesecker, L.G. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine 15: 565–574.Google Scholar
- Hughes, E. (1945) 1971 The Sociological Eye: Selected Papers. Chicago: Aldine-Atherton.Google Scholar
- Keller, E.F. (2000) The Century of the Gene. Cambridge, MA: Harvard University Press.Google Scholar
- Lampland, M. and Star, S.L. (eds.) (2009) Standards and Their Stories: How Quantifying, Classifying, and Formalizing Practices Shape Everyday Life. Ithaca, NY: Cornell University Press.Google Scholar
- Lee, H., Deignan, J.L., Dorrani, N., Strom, S.P., Kantarci, S., Quintero-Rivera, F., Das, K., Toy, T., Harry, B., Yourshaw, M., Fox, M., Fogel, B.L., Martinez-Agosto, J.A., Wong, D.A., Chang, V.Y., Shieh, P.B., Palmer, C.G., Dipple, K.M., Grody, W.W., Vilain, E. and Nelson, S.F. (2014) Clinical exome sequencing for genetic identification of rare mendelian disorders. JAMA 312(18): 1880–1887Google Scholar
- Lippman, A. (1991) Prenatal genetic testing and screening: Construcing needs and reinforcing inequalities. American Journal of Law and Medicine 17: 15–50.Google Scholar
- Lock, M. (2011) Learning to live again with uncertainty: Social repercussions of molecular genomics. In Maheu, L. and Macdonald, R.A. (eds.) Challenging Genetic Determinism: New Perspectives on the Gene and its Multiple Environments. Montreal: McGill-Queen’s University Press.Google Scholar
- Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W.W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K. and Rehm, H.L. (2015) Committee ALQA (2015) standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 17: 405–424.CrossRefGoogle Scholar