All medical information is subject to uncertainty, but the practice of medical genetics is characterized by unique magnitudes and forms of uncertainty. In fact, for many patients, a “positive” screening result still only represents a risk estimate, which is itself irreducibly uncertain. As exome- and genome-scale tests begin to replace smaller panels, and as interpretation driven by clinical indication gives way to the return of “incidental” findings and truly healthy genomes, patients will face an even greater chances of receiving uncertain results. It is therefore critical to understand the psychosocial consequences of returning such results to patients.

Uncertainty can trap patients in an unvalidated sick role with existential concerns about the legitimacy of their diagnosis and lead them to avoid healthcare decision-making. However, uncertainty can also offer hope (a potential “hint”), relief that a feared diagnosis has not been given, and empowerment to evaluate alternative prognoses and engage in research.

The most obvious form of uncertainty in medical genetics is the aptly named variant of uncertain significance, or VUS. These are results for which insufficient scientific evidence exists with which to determine their clinical relevance, and the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) recommend against their use in clinical decision-making. Patients are often counseled to think of a VUS as a placeholder pending reclassification. Most of these results are eventually “downgraded” and labeled benign, which underscores the potential harm in pursuing risk-reducing interventions on their basis. Ethical concerns about justice arise in this domain. In particular, numerous studies have shown that sequencing patients with non-European ancestry yields higher rates of uncertain and misclassified results. Rates of reclassification are also higher for these populations, potentially exacerbating levels of distrust.

The uncertainty that is inherent to genetic test results is both scientific and a feature of the unique interpretations of individuals. Interpretations of variants not only evolve over time but differ significantly among laboratories and between laboratories and clinicians. Patients’ evaluations of uncertain results also contrast with the clinical significance disclosed to them. Patients work to relate uncertain results to their own lives. These interpretations are motivated by a variety of individual characteristics, such as expectations and motivations for testing, health literacy, personal/family history, and uncertainty tolerance. In addition to the receipt of VUS results, patients experience personal uncertainty when learning of carrier status, variants with variable penetrance or phenotype, implications for treatment and prognosis, and recurrence risk, along with the return of so-called “incidental” findings and genes of uncertain significance, meaning whole genes for which insufficient scientific evidence exists with which to determine their clinical relevance.

Empirical studies of patients’ experiences when receiving uncertain genetic information have revealed wide-ranging, and often contradictory, psychosocial responses—positive, negative, and neutral. In any case, longitudinal studies typically suggest that patient affect soon returns to baseline. Findings about patients’ ability to recall and comprehend uncertainty also vary across studies, although the overall impression is that with appropriate counseling, and in emotionally calm conditions, levels of both variables are acceptable for patients to engage in ethically sound decision-making. The variability in the results of these empirical studies may in part be due to a presupposition that uncertainty must be reduced or eliminated. As has been outlined above, though, uncertainty is simultaneously an intrinsic feature of (genomic) medicine and a potentially desirable outcome, with benefits of its own. A shift in counseling practice towards the management of uncertainty is therefore preferable and already underway.

The research for this collection was supported by the NHGRI under award number 1K01HG012408. The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH.