Variant of Uncertain Significance-Related Uncertainty in Breast Cancer Genomics
Purpose of Review
This paper considers the psychosocial implications of variant of uncertain significance (VUS)-derived uncertainty from the perspective of patients and providers and identifies potential uncertainty management strategies that can improve VUS-related clinical care.
Based on the analysis of current research evidence around VUS-related medical management as well as provider and patient experiences of VUS-related uncertainty, we conclude that uncertainty around this new type of medical information is pervasive. Uncertainty appraisal varies across different contextual and situational factors—individual’s cancer diagnosis, provider’s experience with VUS, gene in which VUS has been identified, etc. Most importantly, strategies for uncertainty management that can address much of the VUS-related uncertainty also exist and offer hope for the thousands of VUS that will be returned to patients in genomic medicine clinics.
Uncertain sequencing results, when explained and relayed by experts in the presence of appropriate VUS-related reclassification and re-contact guidelines, increase the likelihood of maximal clinical and psychosocial benefit for patients without causing undue harm.
KeywordsUncertainty Variants of uncertain significance VUS Breast cancer Genomics
Compliance with Ethical Standards
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 4.LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S, Pesaran T, et al. Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genetics in medicine : official journal of the American College of Medical Genetics. 2014;16(11):830–7.CrossRefGoogle Scholar
- 7.Lincoln SE, Yang S, Cline MS, Kobayashi Y, Zhang C, Topper S, et al. Consistency of BRCA1 and BRCA2 variant classifications among clinical diagnostic laboratories. JCO precision oncology. 2017;1.Google Scholar
- 8.Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy M, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur D, Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–291.Google Scholar
- 9.Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002;20(6):1480–90.CrossRefGoogle Scholar
- 10.Weitzel JN, Lagos V, Blazer KR, Nelson R, Ricker C, Herzog J, et al. Prevalence of BRCA mutations and founder effect in high-risk Hispanic families. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005;14(7):1666–71.CrossRefGoogle Scholar
- 11.Nanda R, Schumm LP, Cummings S, Fackenthal JD, Sveen L, Ademuyiwa F, et al. Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. Jama. 2005;294(15):1925–33.CrossRefGoogle Scholar
- 16.Elsayegh N, Webster RD, Gutierrez Barrera AM, Lin H, Kuerer HM, Litton JK, et al. Contralateral prophylactic mastectomy rate and predictive factors among patients with breast cancer who underwent multigene panel testing for hereditary cancer. Cancer medicine. 2018;7(6):2718–26.CrossRefGoogle Scholar
- 22.Kurian AW, Li Y, Hamilton AS, Ward KC, Hawley ST, Morrow M, et al. Gaps in incorporating germline genetic testing into treatment decision-making for early-stage breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2017;35(20):2232–9.CrossRefGoogle Scholar
- 26.Scherr CL, Lindor NM, Malo TL, Couch FJ, Vadaparampil ST. A preliminary investigation of genetic counselors' information needs when receiving a variant of uncertain significance result: a mixed methods study. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(9):739–46.CrossRefGoogle Scholar
- 30.Vos J, Gomez-Garcia E, Oosterwijk JC, Menko FH, Stoel RD, van Asperen CJ, et al. Opening the psychological black box in genetic counseling. The psychological impact of DNA testing is predicted by the counselees’ perception, the medical impact by the pathogenic or uninformative BRCA1/2-result. Psycho-oncology. 2012;21(1):29–42.CrossRefGoogle Scholar
- 31.O'Neill SC, DeMarco T, Peshkin BN, Rogers S, Rispoli J, Brown K, et al. Tolerance for uncertainty and perceived risk among women receiving uninformative BRCA1/2 test results. American journal of medical genetics Part C, Seminars in medical genetics. 2006;142c(4):251–9.Google Scholar
- 32.van Dijk S, Timmermans DR, Meijers-Heijboer H, Tibben A, van Asperen CJ, Otten W. Clinical characteristics affect the impact of an uninformative DNA test result: the course of worry and distress experienced by women who apply for genetic testing for breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(22):3672–7.CrossRefGoogle Scholar
- 34.Clift K, Macklin S, Halverson C, McCormick JB, Abu Dabrh AM, Hines S. Patients’ views on variants of uncertain significance across indications. Journal of community genetics. 2019.Google Scholar
- 36.Richter S, Haroun I, Graham TC, Eisen A, Kiss A, Warner E. Variants of unknown significance in BRCA testing: impact on risk perception, worry, prevention and counseling. Annals of oncology : official journal of the European Society for Medical Oncology. 2013;24 Suppl 8:viii69-viii74.CrossRefGoogle Scholar
- 37.•• Makhnoon S, Shirts BH, Bowen DJ. Patients’ perspectives of variants of uncertain significance and strategies for uncertainty management. J Genet Couns. 2019. This paper outlines a provisional VUS-related uncertainty management strategy.Google Scholar
- 40.Appelbaum PS, Parens E, Berger SM, Chung WK, Burke W. Is there a duty to reinterpret genetic data? The ethical dimensions. Genetics in medicine : official journal of the American College of Medical Genetics. 2019.Google Scholar