Skip to main content

Multigene Cancer Panels: Implications for Pre- and Post-test Genetic Counseling

Current Genetic Medicine Reports volume 7, pages 169–179 (2019)Cite this article

Abstract

Purpose of Review

The availability of multigene cancer panel testing (MCPT) has revolutionized the care of individuals and families at risk for hereditary cancer. This review discusses fundamental components of genetic counseling, test selection, result interpretation, and follow-up related to MCPT.

Recent Findings

Routine use of MCPT increases the diagnostic yield for major hereditary cancers such as breast, ovarian, and colon, with the identification of pathogenic variants in high- and moderate-penetrance genes. In addition, the larger the panel, the more likely one or more variants of uncertain significance will be identified. Furthermore, although index cases who test negative after multigene panel testing may derive some reassurance about hereditary risk, assessment and management based on personal and family history are the keys.

Summary

Given the complexity of MCPT, pre- and post-test genetic counseling approaches have been adapted to optimize the delivery of information and support to patients and their families.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Phillips KA, Deverka PA, Hooker GW, Douglas MP. Genetic test availability and spending: where are we now? Where are we going? Health Aff (Millwood). 2018;37:710–6. https://doi.org/10.1377/hlthaff.2017.1427.

    Article  Google Scholar 

  2. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004;4:665–76. https://doi.org/10.1038/nrc1431.

    CAS  Article  PubMed  Google Scholar 

  3. Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP. Milestones of Lynch syndrome: 1895–2015. Nat Rev Cancer. 2015;15:181–94. https://doi.org/10.1038/nrc3878.

    CAS  Article  PubMed  Google Scholar 

  4. •• Hooker GW, Clemens KR, Quillin J, Vogel Postula KJ, Summerour P, Nagy R, et al. Cancer genetic counseling and testing in an era of rapid change. J Genet Couns. 2017;26:1244–53. https://doi.org/10.1007/s10897-017-0099-2. The authors report the results of a survey of genetic counselors regarding their use of multigene panel testing after patents on theBRCAgenes were lifted in 2013.

    Article  PubMed  Google Scholar 

  5. Kurian AW, Ward KC, Hamilton AS, Deapen DM, Abrahamse P, Bondarenko I, et al. Uptake, results, and outcomes of germline multiple-gene sequencing after diagnosis of breast cancer. JAMA Oncol. 2018;4:1066–72. https://doi.org/10.1001/jamaoncol.2018.0644.

    Article  PubMed  PubMed Central  Google Scholar 

  6. • Bradbury AR, Patrick-Miller L, Long J, Powers J, Stopfer J, Forman A, et al. Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility. Genet Med. 2015;17:485–92. https://doi.org/10.1038/gim.2014.134. This paper describes the development of a new model of genetic counseling for patients undergoing multigene panel testing.

    Article  PubMed  Google Scholar 

  7. Domchek SM, Bradbury A, Garber JE, Offit K, Robson ME. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol. 2013;31:1267–70. https://doi.org/10.1200/JCO.2012.46.9403.

    Article  PubMed  Google Scholar 

  8. Lundy MG, Forman A, Valverde K, Kessler L. An investigation of genetic counselors’ testing recommendations: pedigree analysis and the use of multiplex breast cancer panel testing. J Genet Couns. 2014;23:618–32. https://doi.org/10.1007/s10897-014-9692-9.

    Article  PubMed  Google Scholar 

  9. Esteban I, Lopez-Fernandez A, Balmaña J. A narrative overview of the patients’ outcomes after multigene cancer panel testing, and a thorough evaluation of its implications for genetic counselling. Eur J Med Genet. 2019;62:342–9. https://doi.org/10.1016/j.ejmg.2018.11.027.

    CAS  Article  PubMed  Google Scholar 

  10. Berliner JL, Fay AM, Cummings SA, Burnett B, Tillmanns T. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns. 2013;22:155–63. https://doi.org/10.1007/s10897-012-9547-1.

    Article  PubMed  Google Scholar 

  11. Forman A, Schwartz S. Guidelines-based cancer risk assessment. Semin Oncol Nurs. 2019;35:34–46. https://doi.org/10.1016/j.soncn.2018.12.010.

    Article  PubMed  Google Scholar 

  12. Powers J, Stopfer JE. Risk assessment, genetic counseling, and clinical care for hereditary breast cancer. J Obstet Gynecol Neonatal Nurs. 2014;43:361–73. https://doi.org/10.1111/1552-6909.12304.

    Article  PubMed  Google Scholar 

  13. •• Daly MB, Pilarski R, Berry MP, Buys SS, Friedman S, Garber JE, et al. Genetic/familial high-risk assessment: breast and ovarian. NCCN [Internet]. 2019; Version 3. Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed 03 Sept 2019. National guidelines about the identification and management of individuals with or at risk for hereditary breast and ovarian cancer.

  14. •• Provenzale D, Gupta S, Ahnen DJ, Blanco AM, Bray TH, Chung DC, et al. Genetic/familial high-risk assessment: colorectal. NCCN [Internet]. 2019; Version 1. Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed 03 Sept 2019. National guidelines about the identification and management of individuals with or at risk for hereditary colorectal cancer.

  15. Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL. Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70–87. https://doi.org/10.1038/gim.2014.147.

    Article  PubMed  Google Scholar 

  16. Bradbury AR, Patrick-Miller L, Domchek S. Multiplex genetic testing: reconsidering utility and informed consent in the era of next-generation sequencing. Genet Med. 2014;17:97–8. https://doi.org/10.1038/gim.2014.85.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Flores KG, Steffen LE, McLouth CJ, Vicuña BE, Gammon A, Kohlmann W, et al. Factors associated with interest in gene-panel testing and risk communication preferences in women from BRCA1/2 negative families. J Genet Couns. 2017;26:480–90. https://doi.org/10.1007/s10897-016-0001-7.

    Article  PubMed  Google Scholar 

  18. Fecteau H, Vogel KJ, Hanson K, Morrill-Cornelius S. The evolution of cancer risk assessment in the era of next generation sequencing. J Genet Couns. 2014;23:633–9. https://doi.org/10.1007/s10897-014-9714-7.

    Article  PubMed  Google Scholar 

  19. Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190–6. https://doi.org/10.1001/jamaoncol.2017.0424.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Easton DF, Pharoah PDP, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372:2243–57. https://doi.org/10.1056/NEJMsr1501341.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Kurian AW, Antoniou AC, Domchek SM. Refining breast cancer risk stratification: additional genes, additional information. Am Soc Clin Oncol Educ Book. 2016:44–56. https://doi.org/10.14694/edbk_158817.

    Article  Google Scholar 

  22. •• Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13:581–8. https://doi.org/10.1038/nrclinonc.2016.90. This paper describes the counseling framework for cancer risks high- vs. moderate-risk genes and management considerations for moderate risk cancer genes.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305:2304–10. https://doi.org/10.1001/jama.2011.743.

    CAS  Article  PubMed  Google Scholar 

  24. Hall MJ, Obeid EI, Schwartz SC, Mantia-Smaldone G, Forman AD, Daly MB. Genetic testing for hereditary cancer predisposition: BRCA1/2, Lynch syndrome, and beyond. Gynecol Oncol. 2016;140:565–74. https://doi.org/10.1016/j.ygyno.2016.01.019.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Update on hereditary colorectal cancer: improving the clinical utility of multigene panel testing. Clin Colorectal Cancer. 2018;17:e293–305. https://doi.org/10.1016/j.clcc.2018.01.001.

    Article  PubMed  Google Scholar 

  26. Lu H-M, Li S, Black MH, Lee S, Hoiness R, Wu S, et al. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. 2018. https://doi.org/10.1001/jamaoncol.2018.2956.

    Article  PubMed  Google Scholar 

  27. Giri VN, Hegarty SE, Hyatt C, O’Leary E, Garcia J, Knudsen KE, et al. Germline genetic testing for inherited prostate cancer in practice: implications for genetic testing, precision therapy, and cascade testing. Prostate. 2019;79:333–9. https://doi.org/10.1002/pros.23739.

    CAS  Article  PubMed  Google Scholar 

  28. •• Lee K, Seifert BA, Shimelis H, Ghosh R, Crowley SB, Carter NJ, et al. Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels. Genet Med. 2019;21:1479–506. https://doi.org/10.1038/s41436-018-0361-5. This paper evaluates gene-disease association for 31 genes commonly offered on multigene cancer panel tests.

    CAS  Article  Google Scholar 

  29. •• Rosenthal ET, Bernhisel R, Brown K, Kidd J, Manley S. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genet. 2017;218–219:58–68. https://doi.org/10.1016/j.cancergen.2017.09.003. This study reports on the outcome of a broad 25-gene cancer panel test in a consecutive series of 252,223 individuals.

    CAS  Article  PubMed  Google Scholar 

  30. •• Mersch J, Brown N, Pirzadeh-Miller S, Mundt E, Cox HC, Brown K, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320:1266–74. https://doi.org/10.1001/jama.2018.13152. The authors found that of 2048 reclassified variants, over 91% of were downgraded to benign or likely benign and 8.7% were upgraded to pathogenic or likely pathogenic.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Slavin TP, Van Tongeren LR, Behrendt CE, Solomon I, Rybak C, Nehoray B, et al. Prospective study of cancer genetic variants: variation in rate of reclassification by ancestry. J Natl Cancer Inst. 2018;110:1059–66. https://doi.org/10.1093/jnci/djy027.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Szender JB, Kaur J, Clayback K, Hutton ML, Mikkelson J, Odunsi K, et al. Breadth of genetic testing selected by patients at risk of hereditary breast and ovarian cancer. Int J Gynecol Cancer. 2018;28:26–33. https://doi.org/10.1097/IGC.0000000000001122.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Domchek SM. Risk-reducing mastectomy in BRCA1 and BRCA2 mutation carriers: a complex discussion. JAMA. 2019;321:27. https://doi.org/10.1001/jama.2018.18942.

    Article  PubMed  Google Scholar 

  34. Finch APM, Lubinski J, Møller P, Singer CF, Karlan B, Senter L, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32:1547–53. https://doi.org/10.1200/JCO.2013.53.2820.

    Article  PubMed  PubMed Central  Google Scholar 

  35. De Vos Tot Nederveen Cappel WH, Järvinen HJ, Lynch PM, Engel C, Mecklin J-P, Vasen HFA. Colorectal surveillance in Lynch syndrome families. Familial Cancer. 2013;12:261–5. https://doi.org/10.1007/s10689-013-9631-1.

    CAS  Article  PubMed  Google Scholar 

  36. Henn J, Spier I, Adam RS, Holzapfel S, Uhlhaas S, Kayser K, et al. Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes. Hered Cancer Clin Pract. 2019;17:5. https://doi.org/10.1186/s13053-018-0102-4.

    Article  PubMed  PubMed Central  Google Scholar 

  37. •• O’Leary E, Iacoboni D, Holle J, Michalski ST, Esplin ED, Yang S, et al. Expanded gene panel use for women with breast cancer: identification and intervention beyond breast cancer risk. Ann Surg Oncol. 2017;24:3060–6. https://doi.org/10.1245/s10434-017-5963-7. This study reports on clinician ordering patterns for MCPT and increasing diagnostic and clinical yield with broader panel testing.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Ricker C, Culver JO, Lowstuter K, Sturgeon D, Sturgeon JD, Chanock CR, et al. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort. Cancer Gene Ther. 2016;209:130–7. https://doi.org/10.1016/j.cancergen.2015.12.013.

    CAS  Article  Google Scholar 

  39. •• Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016;18:823–32. https://doi.org/10.1038/gim.2015.166. This study reviewed results on 10,000 patients tested by MGPT and found that individuals often had PVs identified in genes not consistent with family history.

    CAS  Article  PubMed  Google Scholar 

  40. Genetic Testing Registry (GTR) - NCBI [Internet]. [cited 2019]. Available from: https://www.ncbi.nlm.nih.gov/gtr/. Accessed 03 Sept 2019.

  41. Robson ME, Bradbury AR, Arun B, Domchek SM, Ford JM, Hampel HL, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. JCO. 2015;33:3660–7. https://doi.org/10.1200/JCO.2015.63.0996.

    CAS  Article  Google Scholar 

  42. Medendorp NM, Hillen MA, Murugesu L, Aalfs CM, Stiggelbout AM, Smets EMA. Uncertainty in consultations about genetic testing for cancer: an explorative observational study. Patient Educ Couns. 2018;101:2083–9. https://doi.org/10.1016/j.pec.2018.08.002.

    Article  PubMed  Google Scholar 

  43. Courtney E, Li S-T, Shaw T, Chen Y, Allen JC, Ngeow J. Predictors of next-generation sequencing panel selection using a shared decision-making approach. NPJ Genom Med. 2018;3:11. https://doi.org/10.1038/s41525-018-0050-y.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Lynce F, Isaacs C. How far do we go with genetic evaluation? Gene, panel, and tumor testing. Am Soc Clin Oncol Educ Book. 2016;35:e72–8. https://doi.org/10.1200/EDBK_160391.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Okur V, Chung WK. The impact of hereditary cancer gene panels on clinical care and lessons learned. Cold Spring Harb Mol Case Stud. 2017;3. https://doi.org/10.1101/mcs.a002154.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Thompson ER, Rowley SM, Li N, McInerny S, Devereux L, Wong-Brown MW, et al. Panel testing for familial breast cancer: calibrating the tension between research and clinical care. JCO. 2016;34:1455–9. https://doi.org/10.1200/JCO.2015.63.7454.

    CAS  Article  Google Scholar 

  47. 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. Genet Med. 2014;16:830–7. https://doi.org/10.1038/gim.2014.40.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Desmond A, Kurian AW, Gabree M, Mills MA, Anderson MJ, Kobayashi Y, et al. Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol. 2015;1:943–51. https://doi.org/10.1001/jamaoncol.2015.2690.

    Article  PubMed  Google Scholar 

  49. 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;10:303–12. https://doi.org/10.1007/s12687-018-0393-1.

    Article  PubMed  Google Scholar 

  50. Bijlsma RM, Wouters RHP, Wessels H, May AM, Ausems MGEM, Voest EE, et al. Managing unsolicited findings in genomics: a qualitative interview study with cancer patients. Psychooncology. 2018;27:1327–33. https://doi.org/10.1002/pon.4676.

    CAS  Article  PubMed  Google Scholar 

  51. Bijlsma RM, Wessels H, Wouters RHP, May AM, Ausems MGEM, Voest EE, et al. Cancer patients’ intentions towards receiving unsolicited genetic information obtained using next-generation sequencing. Familial Cancer. 2018;17:309–16. https://doi.org/10.1007/s10689-017-0033-7.

    CAS  Article  PubMed  Google Scholar 

  52. Kaphingst KA, Ivanovich J, Lyons S, Biesecker B, Dresser R, Elrick A, et al. Preferences for learning different types of genome sequencing results among young breast cancer patients: role of psychological and clinical factors. Transl Behav Med. 2018;8:71–9. https://doi.org/10.1093/tbm/ibx042.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lumish HS, Steinfeld H, Koval C, Russo D, Levinson E, Wynn J, et al. Impact of panel gene testing for hereditary breast and ovarian cancer on patients. J Genet Couns. 2017;26:1116–29. https://doi.org/10.1007/s10897-017-0090-y.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Shannon KM, Rodgers LH, Chan-Smutko G, Patel D, Gabree M, Ryan PD. Which individuals undergoing BRACAnalysis need BART testing? Cancer Gene Ther. 2011;204:416–22. https://doi.org/10.1016/j.cancergen.2011.07.005.

    Article  Google Scholar 

  55. Menko FH, ter Stege JA, van der Kolk LE, Jeanson KN, Schats W, Moha DA, et al. The uptake of presymptomatic genetic testing in hereditary breast-ovarian cancer and Lynch syndrome: a systematic review of the literature and implications for clinical practice. Familial Cancer. 2019;18:127–35. https://doi.org/10.1007/s10689-018-0089-z.

    CAS  Article  PubMed  Google Scholar 

  56. Hampel H. Genetic counseling and cascade genetic testing in Lynch syndrome. Familial Cancer. 2016;15:423–7. https://doi.org/10.1007/s10689-016-9893-5.

    Article  PubMed  Google Scholar 

  57. Thomas MH, Higgs LK, Modesitt SC, Schroen AT, Ring KL, Dillon PM. Cases and evidence for panel testing in cancer genetics: is site-specific testing dead? J Genet Couns. 2019;28:700–7. https://doi.org/10.1002/jgc4.1044.

    Article  PubMed  Google Scholar 

  58. •• Caswell-Jin JL, Gupta T, Hall E, Petrovchich IM, Mills MA, Kingham KE, et al. Racial/ethnic differences in multiple-gene sequencing results for hereditary cancer risk. Genet Med. 2018;20:234–9. https://doi.org/10.1038/gim.2017.96. This paper reports on using a panel for cascade testing and the frequency of identifying a PV other than the familial mutation.

    Article  PubMed  Google Scholar 

  59. Meric-Bernstam F, Brusco L, Daniels M, Wathoo C, Bailey AM, Strong L, et al. Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. Ann Oncol. 2016;27:795–800. https://doi.org/10.1093/annonc/mdw018.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19:4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. Haque MM, Kowtal P, Sarin R. Identification and characterization of TP53 gene allele dropout in Li-Fraumeni syndrome and oral cancer cohorts. Sci Rep. 2018;8:11705. https://doi.org/10.1038/s41598-018-30238-7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. •• Brown S, Puumala S, Leonhard J, Bell M, Flanagan J, Dean LW, et al. Genesurance counseling: genetic counselors’ roles and responsibilities in regards to genetic insurance and financial topics. J Genet Couns. 2018;27:800–13. https://doi.org/10.1007/s10897-017-0180-x. This study reports on “genesurance counseling” and how genetic counselors cover insurance information into pre-test genetic counseling.

    Article  PubMed  Google Scholar 

  63. Wagner C, Murphy L, Harkenrider J, Darilek S, Soto-Torres E, Stein Q, et al. Genesurance counseling: patient perspectives. J Genet Couns. 2018;27:814–22. https://doi.org/10.1007/s10897-018-0211-2.

    Article  PubMed  Google Scholar 

  64. Walcott FL, Dunn BK. Legislation in the genomic era: the Affordable Care Act and genetic testing for cancer risk assessment. Genet Med. 2015;17:962–4. https://doi.org/10.1038/gim.2015.18.

    Article  PubMed  Google Scholar 

  65. Clain E, Trosman JR, Douglas MP, Weldon CB, Phillips KA. Availability and payer coverage of BRCA1/2 tests and gene panels. Nat Biotechnol. 2015;33:900–2. https://doi.org/10.1038/nbt.3322.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Trosman JR, Weldon CB, Douglas MP, Kurian AW, Kelley RK, Deverka PA, et al. Payer coverage for hereditary cancer panels: barriers, opportunities, and implications for the precision medicine initiative. J Natl Compr Cancer Netw. 2017;15:219–28. https://doi.org/10.6004/jnccn.2017.0022.

    Article  Google Scholar 

  67. Prince AER, Roche MI. Genetic information, non-discrimination, and privacy protections in genetic counseling practice. J Genet Couns. 2014;23:891–902. https://doi.org/10.1007/s10897-014-9743-2.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Genetic Information Nondiscrimination Act of 2008 [Internet]. [cited 2019]. Available from: https://www.eeoc.gov/laws/statutes/gina.cfm. Accessed 03 Sept 2019.

  69. Genetic Discrimination [Internet]. Genome.gov. [cited 2019]. Available from: https://www.genome.gov/about-genomics/policy-issues/Genetic-Discrimination. Accessed 03 Sept 2019.

  70. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110:223–62; quiz 263. https://doi.org/10.1038/ajg.2014.435.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Boland PM, Yurgelun MB, Boland CR. Recent progress in Lynch syndrome and other familial colorectal cancer syndromes. CA Cancer J Clin. 2018;68:217–31. https://doi.org/10.3322/caac.21448.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nathan MR, Schmid P. The emerging world of breast cancer immunotherapy. Breast. 2018;37:200–6. https://doi.org/10.1016/j.breast.2017.05.013.

    Article  PubMed  Google Scholar 

  73. Roberts ME, Ranola JMO, Marshall ML, Susswein LR, Graceffo S, Bohnert K, et al. Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol. 2019. https://doi.org/10.1001/jamaoncol.2019.1208.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Van Der Post RS, Vogelaar IP, Carneiro F, Guilford P, Huntsman D, Hoogerbrugge N, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet. 2015;52:361–74. https://doi.org/10.1136/jmedgenet-2015-103094.

    CAS  Article  PubMed  Google Scholar 

  75. Hallowell N, Lawton J, Badger S, Richardson S, Hardwick RH, Caldas C, et al. The psychosocial impact of undergoing Prophylactic Total Gastrectomy (PTG) to manage the risk of Hereditary Diffuse Gastric Cancer (HDGC). J Genet Couns. 2017;26:752–62. https://doi.org/10.1007/s10897-016-0045-8.

    Article  PubMed  Google Scholar 

  76. •• Lowstuter K, Espenschied CR, Sturgeon D, Ricker C, Karam R, LaDuca H, et al. Unexpected CDH1 mutations identified on multigene panels pose clinical management challenges. JCO Precis Oncol. 2017:1–12. https://doi.org/10.1200/PO.16.00021. Authors identified carriers of CDH1 and found that 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria.

  77. •• Harrison SM, Dolinsky JS, Knight Johnson AE, Pesaran T, Azzariti DR, Bale S, et al. Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. Genet Med. 2017;19:1096–104. https://doi.org/10.1038/gim.2017.14. This study reviewed 6,169 variants in ClinVar, of which 88.3% were initially concordant and reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Garcia C, Lyon L, Littell RD, Powell CB. Comparison of risk management strategies between women testing positive for a BRCA variant of unknown significance and women with known BRCA deleterious mutations. Genet Med. 2014;16:896–902. https://doi.org/10.1038/gim.2014.48.

    CAS  Article  PubMed  Google Scholar 

  79. Hoffman-Andrews L. The known unknown: the challenges of genetic variants of uncertain significance in clinical practice. J Law Biosci. 2017;4:648–57. https://doi.org/10.1093/jlb/lsx038.

    Article  PubMed  Google Scholar 

  80. Rhees J, Arnold M, Boland CR. Inversion of exons 1-7 of the MSH2 gene is a frequent cause of unexplained Lynch syndrome in one local population. Familial Cancer. 2014;13:219–25. https://doi.org/10.1007/s10689-013-9688-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. •• Girardi F, Barnes DR, Barrowdale D, Frost D, Brady AF, Miller C, et al. Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study. Genet Med. 2018;20:1575–82. https://doi.org/10.1038/gim.2018.44. This study evaluated 1895 unaffected women who did not inherit a familial pathogenic variant in BRCA1/2. No increased risks for breast or ovarian cancer identified.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Ingham SL, Warwick J, Buchan I, Sahin S, O’Hara C, Moran A, et al. Ovarian cancer among 8,005 women from a breast cancer family history clinic: no increased risk of invasive ovarian cancer in families testing negative for BRCA1 and BRCA2. J Med Genet. 2013;50:368–72. https://doi.org/10.1136/jmedgenet-2013-101607.

    CAS  Article  PubMed  Google Scholar 

  83. •• Reiner AS, Sisti J, John EM, Lynch CF, Brooks JD, Mellemkjær L, et al. Breast cancer family history and contralateral breast cancer risk in young women: An update from the women’s environmental cancer and radiation epidemiology study. J Clin Oncol. 2018;36:1513–20. https://doi.org/10.1200/JCO.2017.77.3424. This study found that breast cancer family history confers a high risk of contralateral breast cancer, even after excluding women with PVs in breast cancer genes.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Provenzale D, Gupta S, Ahnen DJ, Chen L-M, Chung DC, Cooper G, et al. Colorectal cancer screening. NCCN [Internet]. 2019;Version 1. Available from: https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed 03 Sept 2019.

  85. Brentnall AR, Cuzick J, Buist DSM, Bowles EJA. Long-term accuracy of breast cancer risk assessment combining classic risk factors and breast density. JAMA Oncol. 2018;4:e180174. https://doi.org/10.1001/jamaoncol.2018.0174.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Pruthi S, Heisey RE, Bevers TB. Chemoprevention for breast cancer. Ann Surg Oncol. 2015;22:3230–5. https://doi.org/10.1245/s10434-015-4715-9.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Lee AJ, Cunningham AP, Tischkowitz M, Simard J, Pharoah PD, Easton DF, et al. Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. Genet Med. 2016;18:1190–8. https://doi.org/10.1038/gim.2016.31.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ. Clinical use of current polygenic risk scores may exacerbate health disparities. Nat Genet. 2019;51:584–91. https://doi.org/10.1038/s41588-019-0379-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Wald NJ, Old R. The illusion of polygenic disease risk prediction. Genet Med. 2019;21:1705–7. https://doi.org/10.1038/s41436-018-0418-5.

    Article  PubMed  Google Scholar 

  90. Mets S, Tryon R, Veach PM, Zierhut HA. Genetic counselors’ experiences regarding communication of reproductive risks with autosomal recessive conditions found on cancer panels. J Genet Couns. 2016;25:359–72. https://doi.org/10.1007/s10897-015-9892-y.

    Article  PubMed  Google Scholar 

  91. Bradbury AR, Patrick-Miller LJ, Egleston BL, DiGiovanni L, Brower J, Harris D, 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. https://doi.org/10.1038/gim.2015.19.

    Article  PubMed  Google Scholar 

  92. Esteban I, Vilaró M, Adrover E, Angulo A, Carrasco E, Gadea N, et al. Psychological impact of multigene cancer panel testing in patients with a clinical suspicion of hereditary cancer across Spain. Psycho-Oncology. 2018;27:1530–7. https://doi.org/10.1002/pon.4686.

    CAS  Article  PubMed  Google Scholar 

  93. 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. Psycho-Oncology. 2008;17:822–30. https://doi.org/10.1002/pon.1311.

    Article  PubMed  Google Scholar 

  94. •• Reuter C, Chun N, Pariani M, Hanson-Kahn A. Understanding variants of uncertain significance in the era of multigene panels: through the eyes of the patient. J Genet Couns. 2019. https://doi.org/10.1002/jgc4.1130. This study used a semi-structured interview on adults who had a VUS identified on a multi-gene panel and found participants understood the lack of clinical significance of a VUS, yet often interpreted the etiologic significance of a VUS within the context of the personal and family history.

  95. Giri VN, Obeid E, Hegarty SE, Gross L, Bealin L, Hyatt C, et al. Understanding of multigene test results among males undergoing germline testing for inherited prostate cancer: implications for genetic counseling. Prostate. 2018;78:879–88. https://doi.org/10.1002/pros.23535.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Savannah Binion, BA, for assistance with manuscript preparation and editing.

Author information

Authors and Affiliations

  1. ProHealth Care, Milwaukee, WI, USA

    Margo C. Grady

  2. MedStar Georgetown University Hospital, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA

    Kavitha A. Kolla

  3. Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA

    Kavitha A. Kolla & Beth N. Peshkin

  4. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Beth N. Peshkin

Authors
  1. Margo C. Grady
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kavitha A. Kolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beth N. Peshkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beth N. Peshkin.

Ethics declarations

Conflict of Interest

Ms. Kolla declares no conflicts of interest.

Ms. Grady reports consulting fees from ActX (Seattle, WA).

Ms. Peshkin reports consulting fees from Clear Genetics, Inc. (San Francisco, CA).

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Counseling and Testing

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Grady, M.C., Kolla, K.A. & Peshkin, B.N. Multigene Cancer Panels: Implications for Pre- and Post-test Genetic Counseling. Curr Genet Med Rep 7, 169–179 (2019). https://doi.org/10.1007/s40142-019-00173-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40142-019-00173-8

Keywords

  • Cancer genetics
  • Genetic counseling
  • Multigene cancer panels
  • Cancer genetic testing