Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis


This study systematically reviewed and synthesized the literature on psychological and clinical outcomes of receiving a variant of uncertain significance (VUS) from multigene panel testing or genomic sequencing. MEDLINE and EMBASE were searched. Two reviewers screened studies and extracted data. Data were synthesized through meta-analysis and meta-aggregation. The search identified 4539 unique studies and 15 were included in the review. Patients with VUS reported higher genetic test–specific concerns on the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale than patients with negative results (mean difference 3.73 [95% CI 0.80 to 6.66] P = 0.0126), and lower than patients with positive results (mean difference −7.01 [95% CI −11.31 to −2.71], P = 0.0014). Patients with VUS and patients with negative results were similarly likely to have a change in their clinical management (OR 1.41 [95% CI 0.90 to 2.21], P = 0.182), and less likely to have a change in management than patients with positive results (OR 0.09 [95% CI 0.05 to 0.19], P < 0.0001). Factors that contributed to how patients responded to their VUS included their interpretation of the result and their health-care provider’s counseling and recommendations. Review findings suggest there may be a need for practice guidelines or clinical decision support tools for VUS disclosure and management.

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Fig. 1: Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA).
Fig. 2: Forest plots from meta-analysis.


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We thank Lusine Abrahamyan and Mark Dobrow for their feedback on the research question, PICOS, and first draft of the manuscript. We thank Agnes Sebastian for her assistance retrieving articles to include in full-text review. C.M. received support from the Research Training Centre at St. Michael’s Hospital, a doctoral award from the Canadian Institutes of Health Research (CIHR, GSD-164222) and a studentship funded by the Canadian Centre for Applied Research in Cancer Control (ARCC); ARCC receives core funding from the Canadian Cancer Society (grant 2015–703549). S.S. was supported by a doctoral award from the Canadian Institutes of Health Research. Y.B. was supported by a CIHR New Investigator Award.

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Mighton, C., Shickh, S., Uleryk, E. et al. Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis. Genet Med (2020).

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  • genetic testing
  • variant of uncertain significance
  • clinical outcomes
  • psychologicaloutcomes
  • systematic review