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.
Subscribe to Journal
Get full journal access for 1 year
only $41.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Richards S, Aziz N, Bale S, et al. 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. Genet Med. 2015;17:405–424.
Buys S, Sandback J, Gammon A, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 2019;123:1721–1730.
Dixon-Salazar TJ, Silhavy JL, Udpa N, et al. Exome sequencing can improve diagnosis and alter patient management. Sci Transl Med. 2012;4:138ra78–138ra78.
Mighton C, Charames G, Wang M, et al. Variant classification changes over time in BRCA1 and BRCA2. Genet Med. 2019;21:2248–2254.
Macklin S, Durand N, Atwal P, Hines S. Observed frequency and challenges of variant reclassification in a hereditary cancer clinic. Genet Med. 2018;20:346–350.
Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320:1266–1274.
Daly MB, Pilarski R, Yurgelun MB, et al. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020. J Natl Compr Canc Netw. 2020;18:380–391.
Culver JO, Brinkerhoff CD, Clague J, et al. Variants of uncertain significance in BRCA testing: evaluation of surgical decisions, risk perception, and cancer distress. Clin Genet. 2013;84:464–472.
O’Neill SC, Rini C, Goldsmith RE, Valdimarsdottir H, Cohen LH, Schwartz MD. Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes. Psychooncology. 2009;18:1088–1096.
Schwartz M, Peshkin B, Hughes C, Main D, Isaacs C, Lerman C. Impact of BRCA1/BRCA2 mutation testing on psychologic distress in a clinic-based sample. J Clin Oncol. 2002;20:514–520.
Vos J, Otten W, van Asperen C, Jansen A, Menko F, Tibben A. The counsellees’ view of an unclassified variant in BRCA1/2: recall, interpretation, and impact on life. Psychooncology. 2008;17:822–830.
Charrois TL. Systematic reviews: what do you need to know to get started? Can J Hosp Pharm. 2015;68:144–148.
Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.
Lockwood C, Munn Z, Porritt K. Qualitative research synthesis: methodological guidance for systematic reviewers utilizing meta-aggregation. Int J Evid Based Healthc. 2015;13:179–187.
Moola S, Munn Z, Tufanaru C, et al. Chapter 7: Systematic reviews of etiology and risk. In: Aromataris E, Munn Z (editors). JBI Manual for Evidence Synthesis. JBI, 2020. https://synthesismanual.jbi.global.
Dixon-Woods M, Agarwal S, Jones D, Young B, Sutton A. Synthesising qualitative and quantitative evidence: a review of possible methods. J Health Serv Res Policy. 2005;10:45–53.
Borenstein M, Hedges L, Higgins J, Rothstein H Introduction to Meta-analysis. John Wiley & Sons, Ltd; 2009.
Cella D, Hughes C, Peterman A, et al. A brief assessment of concerns associated with genetic testing for cancer: the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire. Health Psychol. 2002;21:564–572.
Higgins JPT, Thomas J, Chandler J, et al. (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. www.training.cochrane.org/handbook.
Creamer M, Bell R, Failla S. Psychometric properties of the Impact of Event Scale–Revised. Behav Res Ther. 2003;41:1489–1496.
Munn Z, Dias M, Tufanaru C, et al. Adherence of meta-aggregative systematic reviews to reporting standards and methodological guidance: a methodological review protocol. JBI Database System Rev Implement Rep. 2019;17:444–450.
Bonadies DC, Brierley KL, Barnett RE, et al. Adverse events in cancer genetic testing: the third case series. Cancer J. 2014;20:246–253.
Bradbury AR, Patrick-Miller LJ, Egleston BL, et al. Patient feedback and early outcome data with a novel tiered-binned model for multiplex breast cancer susceptibility testing. Genet Med. 2016;18:25–33.
Burns C, Yeates L, Spinks C, Semsarian C, Ingles J. Attitudes, knowledge and consequences of uncertain genetic findings in hypertrophic cardiomyopathy. Eur J Hum Genet. 2017;25:809–815.
Esteban I, Vilaro M, Adrover E, et al. Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain. Psychooncology. 2018;27:927–34.
Hermel DJ, McKinnon WC, Wood ME, Greenblatt MS. Multi-gene panel testing for hereditary cancer susceptibility in a rural Familial Cancer Program. Fam Cancer. 2017;16:159–166.
Kurian AW, Li Y, Hamilton AS, et al. Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. J Clin Oncol. 2017;35:2232–2239.
Lawal TA, Lewis KL, Johnston JJ, et al. Disclosure of cardiac variants of uncertain significance results in an exome cohort. Clin Genet. 2018;93:1022–1029.
Li ST, Sun S, Lie D, et al. Factors influencing the decision to share cancer genetic results among family members: an in-depth interview study of women in an Asian setting. Psychooncology. 2018;27:998–1004.
Lumish HS, Steinfeld H, Koval C, et al. Impact of panel gene testing for hereditary breast and ovarian cancer on patients. J Genet Couns. 2017;26:1116–1129.
Mauer CB, Pirzadeh-Miller SM, Robinson LD, Euhus DM. The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genet Med. 2014;16:407–412.
Pederson HJ, Gopalakrishnan D, Noss R, Yanda C, Eng C, Grobmyer SR. Impact of multigene panel testing on surgical decision making in breast cancer patients. J Am Coll Surg. 2018;226:560–565.
Predham S, Hathaway J, Hulait G, Arbour L, Lehman A. Patient recall, interpretation, and perspective of an inconclusive long QT syndrome genetic test result. J Genet Couns. 2017;26:150–158.
Skinner D, Roche MI, Weck KE, et al. “Possibly positive or certainly uncertain?”: participants’ responses to uncertain diagnostic results from exome sequencing. Genet Med. 2018;20:313–319.
Solomon I, Harrington E, Hooker G, et al. Lynch syndrome limbo: patient understanding of variants of uncertain significance. J Genet Couns. 2017;26:866–877.
Wynn J, Holland DT, Duong J, Ahimaz P, Chung WK. Examining the psychosocial impact of genetic testing for cardiomyopathies. J Genet Couns. 2018;27:927–934.
Li M, Bennette CS, Amendola LM, et al. The Feelings About genomiC Testing Results (FACToR) Questionnaire: development and preliminary validation. J Genet Couns. 2019;28:477–490.
Robinson JO, Wynn J, Biesecker B, et al. Psychological outcomes related to exome and genome sequencing result disclosure: a meta-analysis of seven Clinical Sequencing Exploratory Research (CSER) Consortium studies. Genet Med. 2019;21:2781–2790.
Semaka A, Balneaves LG, Hayden MR. “Grasping the grey”: patient understanding and interpretation of an intermediate allele predictive test result for Huntington disease. J Genet Couns. 2013;22:200–217.
Medendorp NM, Hillen MA, Murugesu L, Aalfs CM, Stiggelbout AM, Smets EMA. Uncertainty related to multigene panel testing for cancer: a qualitative study on counsellors’ and counselees’ views. J Community Genet. 2019;10:303–312.
Newson AJ, Leonard SJ, Hall A, Gaff CL. Known unknowns: building an ethics of uncertainty into genomic medicine. BMC Med Genomics. 2016;9:57.
Dheensa S, Carrieri D, Kelly S, et al. A ‘joint venture’ model of recontacting in clinical genomics: challenges for responsible implementation. Eur J Med Genet. 2017;60:403–409.
Carrieri D, Dheensa S, Doheny S, et al. Recontacting in clinical practice: the views and expectations of patients in the United Kingdom. Eur J Hum Genet. 2017;25:1106–1112.
Bombard Y, Brothers KB, Fitzgerald-Butt S, et al. The responsibility to recontact research participants after reinterpretation of genetic and genomic research results. Am J Hum Genet. 2019;104:578–595.
David KL, Best RG, Brenman LM, et al. Patient re-contact after revision of genomic test results: points to consider-a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019;21:769–771.
Bombard Y, Mighton C. Recontacting clinical genetics patients with reclassified results: equity and policy challenges. Eur J Hum Genet. 2019;27:505–506.
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.
The authors declare no conflicts of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Prospero Registration: CRD42018093737
About this article
Cite this article
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). https://doi.org/10.1038/s41436-020-00957-2
- genetic testing
- variant of uncertain significance
- clinical outcomes
- systematic review