Abstract
As genomic sequencing expands into more areas of patient care, an increasing number of patients learn of the variants of uncertain significance (VUSs) that they carry. Understanding the potential psychosocial consequences of the disclosure of a VUS can help inform pre- and post-test counseling discussions. Medical uncertainty in general elicits a variety of responses from patients, particularly in the growing field of medical genetics and genomics. It is important to consider patients’ responses to the ambiguous nature of VUSs across different indications and situational contexts. Genetic counselors and other providers ordering genetic testing should be prepared for the possibility of their patients’ misinterpretation of such results. Pre-test counseling should include a discussion of the possibility of VUSs and what it would mean for the patient’s care and its potential psychosocial impacts. When a VUS is found, post-test counseling should include additional education and a discussion of the variant’s implications and medical management recommendations based on the results. These discussions may help temper subjective interpretations, unrealistic views, and decisional regret.
Similar content being viewed by others
References
Ackerman MJ (2015) Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm 12:2325–2331. https://doi.org/10.1016/j.hrthm.2015.07.002
Appelbaum P, Lidz C (2008) Oxford textbook of clinical research ethics: 633
Berg JS et al (2013) Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet Med 15:860
Biesecker BB, Klein W, Lewis KL, Fisher TC, Wright MF, Biesecker LG, Han PK (2014) How do research participants perceive “uncertainty” in genome sequencing?. Genet Med 16(12):977–980
Bradbury AR et al (2012) When parents disclose BRCA1/2 test results: their communication and perceptions of offspring response. Cancer 118:3417–3425. https://doi.org/10.1002/cncr.26471
Burns C, Yeates L, Spinks C, Semsarian C, Ingles J (2017) Attitudes, knowledge and consequences of uncertain genetic findings in hypertrophic cardiomyopathy. Eur J Hum Genet 25:809. https://doi.org/10.1038/ejhg.2017.66
Daly MB, Barsevick A, Miller SM, Buckman R, Costalas J, Montgomery S, Bingler R (2001) Communicating genetic test results to the family: a six-step. Fam Community Health 24:13–26
Dewey FE, Grove ME, Pan C, Goldstein BA, Bernstein JA, Chaib H, Merker JD, Goldfeder RL, Enns GM, David SP, Pakdaman N, Ormond KE, Caleshu C, Kingham K, Klein TE, Whirl-Carrillo M, Sakamoto K, Wheeler MT, Butte AJ, Ford JM, Boxer L, Ioannidis JPA, Yeung AC, Altman RB, Assimes TL, Snyder M, Ashley EA, Quertermous T (2014) Clinical interpretation and implications of whole-genome sequencing. Whole-Genome Sequencing Whole-Genome Sequencing. JAMA 311:1035–1045. https://doi.org/10.1001/jama.2014.1717
Grover S, Stoffel EM, Mercado RC, Ford BM, Kohlman WK, Shannon KM, Conrad PG, Blanco AM, Terdiman JP, Gruber SB, Chung DC, Syngal S (2009) Colorectal cancer risk perception on the basis of genetic test results in individuals at risk for Lynch syndrome. J Clin Oncol 27:3981–3986. https://doi.org/10.1200/JCO.2008.18.6940
Han PK et al (2017) A taxonomy of medical uncertainties in clinical genome sequencing. Genet Med 19:918
Hargraves I, LeBlanc A, Shah ND, Montori VM (2016) Shared decision making: the need for patient-clinician conversation, not just information. Health Aff (Project Hope) 35(4):627–629
Howard HC, Iwarsson E (2018) Mapping uncertainty in genomics. J Risk Res 21:117–128
Jamal L et al (2017) When bins blur: patient perspectives on categories of results from clinical whole genome sequencing. AJOB Empirical Bioethics 8:82–88. https://doi.org/10.1080/23294515.2017.1287786
Jez S, Martin M, South S, Vanzo R, Rothwell E (2015) Variants of unknown significance on chromosomal microarray analysis: parental perspectives. J Commun Genet 6:343–349
Johnson KJ et al (2016) The genomic novel and priority mapping tool: using empathic design to develop innovative patient-centered decision-making tools for the genomic testing experience. J Genet Disord Genet Rep:2016
Kaphingst KA et al (2016) Preferences for return of incidental findings from genome sequencing among women diagnosed with breast cancer at a young age. Clin Genet 89:378–384. https://doi.org/10.1111/cge.12597
Katz SJ, Ward KC, Hamilton AS, Abrahamse P, Hawley ST, Kurian AW (2018) Association of germline genetic test type and results with patient cancer worry after diagnosis of breast cancer. JCO Precis Oncol:1–8. https://doi.org/10.1200/po.18.00225
Kiedrowski LA, Owens KM, Yashar BM, Schuette JL (2016) Parents’ perspectives on variants of uncertain significance from chromosome microarray analysis. J Genet Couns 25:101–111
Landrum MJ et al (2017) ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 46:D1062–D1067
Lawal T et al. (2018) Disclosure of cardiac variants of uncertain significance results in an exome cohort clinical genetics
Lazaridis KN et al. (2016) Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine clinic: the mayo clinic experience. In: Mayo Clinic Proceedings, vol 3. Elsevier, pp 297–307
Lumish HS, Steinfeld H, Koval C, Russo D, Levinson E, Wynn J, Duong J, Chung WK (2017) Impact of panel gene testing for hereditary breast and ovarian cancer on patients. J Genet Couns 26:1116–1129. https://doi.org/10.1007/s10897-017-0090-y
Macklin SK, Jackson JL, Atwal PS, Hines SL (2018a) Physician interpretation of variants of uncertain significance. Familial cancer 1-6
Macklin S, Laney D, Lisi E, Atherton A, Smith E (2018b) The psychosocial impact of carrying a debated variant in the gla gene. J Genet Couns 27:217–224. https://doi.org/10.1007/s10897-017-0139-y
Madeo AC, O’brien KE, Bernhardt BA, Biesecker BB (2012) Factors associated with perceived uncertainty among parents of children with undiagnosed medical conditions. Am J Med Genet A 158:1877–1884
Makhnoon S, Garrett LT, Burke W, Bowen DJ, Shirts BH (2018) Experiences of patients seeking to participate in variant of uncertain significance reclassification research. J Commun Genet. https://doi.org/10.1007/s12687-018-0375-3
Makhnoon S, Shirts BH, Bowen DJ (2019) Patients' perspectives of variants of uncertain significance and strategies for uncertainty management. J. Genet. Couns. 28(2):313–325
Marron JM et al (2016) Patient/parent perspectives on genomic tumor profiling of pediatric solid tumors: the individualized cancer therapy (iCat) experience. Pediatr Blood Cancer 63:1974–1982. https://doi.org/10.1002/pbc.26137
Mishel MH (1988) Uncertainty in illness. J Nurs Scholarsh 20:225–232
Newson AJ, Leonard SJ, Hall A, Gaff CL (2016) Known unknowns: building an ethics of uncertainty into genomic medicine. BMC Med Genomics 9:57. https://doi.org/10.1186/s12920-016-0219-0
O'Neill SC, Rini C, Goldsmith RE, Valdimarsdottir H, Cohen LH, Schwartz MD (2009) Distress among women receiving uninformative BRCA1/2 results: 12-month outcomes. Psycho-Oncology 18:1088–1096
Pyeritz RE (2017) A brief history of uncertainty in medical genetics and genomics. In: History of Human Genetics. Springer, pp 133–142
Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL, Plon SE, Ramos EM, Sherry ST, Watson MS, ClinGen (2015) ClinGen—The Clinical Genome Resource. N Engl J Med 372:2235–2242. https://doi.org/10.1056/NEJMsr1406261
Reiff M, Bernhardt BA, Mulchandani S, Soucier D, Cornell D, Pyeritz RE, Spinner NB (2012) “What does it mean?”: uncertainties in understanding results of chromosomal microarray testing. Genet Med 14:250. https://doi.org/10.1038/gim.2011.52
Resta R (2014) VUS iz dos? Suggestions for a reasonable policy on reporting genetic variants of unknown significance
Richards S et al (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. Genet Med 17:405
Richter S, Haroun I, Graham T, Eisen A, Kiss A, Warner E (2013) Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and counseling. Ann Oncol 24:viii69–viii74
Skinner D et al (2017) “Possibly positive or certainly uncertain?”: participants’ responses to uncertain diagnostic results from exome sequencing. Genet Med 20:313. https://doi.org/10.1038/gim.2017.135
Solomon I, Harrington E, Hooker G, Erby L, Axilbund J, Hampel H, Semotiuk K, Blanco A, Klein WMP, Giardiello F, Leonard L (2017) Lynch syndrome limbo: patient understanding of variants of uncertain significance. J Genet Couns 26:866–877
Turbitt E, Halliday JL, Armor DJ, Metcalfe SA (2015) Preferences for results from genomic microarrays: comparing parents and health care providers. Clin Genet 87:21–29. https://doi.org/10.1111/cge.12398
Werner-Lin A, Zaspel L, Carlson M, Mueller R, Walser SA, Desai R, Bernhardt BA (2018) Gratitude, protective buffering, and cognitive dissonance: how families respond to pediatric whole exome sequencing in the absence of actionable results. Am J Med Genet A 176:578–588. https://doi.org/10.1002/ajmg.a.38613
Wilkins EJ, Archibald AD, Sahhar MA, White SM (2016) “It wasn't a disaster or anything”: parents’ experiences of their child's uncertain chromosomal microarray result. Am J Med Genet A 170:2895–2904. https://doi.org/10.1002/ajmg.a.37838
Wynn J, Holland DT, Duong J, Ahimaz P, Chung WK, (2018a) Examining the psychosocial impact of genetic testing for cardiomyopathies. J Genet Couns 27(4):927–934
Wynn J, Ottman R, Duong J, Wilson AL, Ahimaz P, Martinez J, Rabin R, Rosen E, Webster R, Au C, Cho MT, Egan C, Guzman E, Primiano M, Shaw JE, Sisson R, Klitzman RL, Appelbaum PS, Lichter-Konecki U, Anyane-Yeboa K, Iglesias A, Chung WK (2018b) Diagnostic exome sequencing in children: a survey of parental understanding, experience and psychological impact. Clin Genet 93:1039–1048
Yushak ML et al (2016) Patient preferences regarding incidental genomic findings discovered during tumor profiling. Cancer 122:1588–1597
Acknowledgements
This work was supported by the Mayo Clinic Center for Individualized Medicine.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
This work was supported by the Mayo Clinic Center for Individualized Medicine.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in the referenced studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the referenced studies.
This article does not contain any studies with human participants performed by any of the authors.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Clift, K., Macklin, S., Halverson, C. et al. Patients’ views on variants of uncertain significance across indications. J Community Genet 11, 139–145 (2020). https://doi.org/10.1007/s12687-019-00434-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12687-019-00434-7