Patients' perspectives of variants of uncertain significance and strategies for uncertainty management

Abstract

Variants of uncertain significance (VUS) are a well‐recognized source of uncertainty in genomic medicine. Despite the existence of straightforward clinical management recommendations, patients report feeling anxiety, worry, and uncertainty in response to VUS. We report the first structured analysis of patient perspectives of VUS‐related uncertainty in genome sequencing using Han's taxonomy of genomic uncertainty. We conducted in‐depth semi‐structured interviews with 11 patients to elicit their thoughts regarding implications of the result for themselves and their family members. Patients' primary concern with VUS‐related uncertainty involved personal and practical issues as they directly inform health‐care decisions. Patients demonstrated good understanding of the epistemic nature of VUS uncertainty—that information about such variant is currently unknown. However, between‐provider discordance in explanations of the implication of this uncertainty for patients' diagnosis, prognosis, and therapy was a major contributor to the overall experience of uncertainty. Strategies for uncertainty reduction involved periodically checking back for reclassification and receiving concordant and clear recommendation from providers. Other proactive strategies of uncertainty reduction—such as information seeking and reading the genetic test report—were not helpful. Collectively, these findings offer previously unreported insight into uncertainty management strategies used by patients which have the potential to guide clinical management practices.

Psychosocial problems in women attending French, German and Spanish genetics clinics before and after targeted or multigene testing results: an observational prospective study

“…Recommendations for managing VUS have recently been issued, advising that counselees may be recontacted if a VUS is reclassified into ‘clinically actionable’ or ‘definitively non-pathogenic’ 18. Adherence to these guidelines may avoid detrimental between-clinicians discordant messages 54. This information imparted to counselees may have led them to put their concerns and expectations on hold while non-carriers, mostly individuals receiving an uninformative result in these samples, remained uncertain about their cancer risk status (eg, how to explain one’s BC diagnostic) and its medical consequences.…”

Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancers

“…Only already established pathogenic variants are often reported and considered in standard clinical processes, necessarily leaving outside genetic information of still unknown significance. This leads to the underestimation of patients' genetic data and, possibly, creates confusion in patients when receiving notice of undefined variants [13,15,36,37]. Furthermore, Capoluongo and colleagues brought to the attention another issue: the different consideration given to somatic and germline mutations and their testing.…”

Uncertainty in health care: Towards a more systematic program of research

“…For example, we recently applied the taxonomy to clinical genome sequencing, expanding its precision to identify specific sources and issues of uncertainty pertaining to this technology [36]. Applied in this way, the taxonomy can provide a a useful starting point to understand the uncertainties manifest in specific clinical problems and has begun to be applied in this manner [36][37][38][39][40][41], although its broader value remains to be established.…”