Historically, genetic testing (and billing) for hereditary cancer risk was essentially performed gene by gene, with clinicians ordering testing only for the genes most likely to explain a patient’s or family’s cancer presentation, with laboratories typically charging $1,000 to $1,500 for each gene that was sequenced. Given the expense, only patients at high risk of having a hereditary syndrome were offered testing. With the introduction of next-generation sequencing technologies, however, laboratories are able to test for multiple genes at the same time with greater efficiency, significantly decreased costs, and relatively little increased expense when adding additional genes. This has drastically altered clinical practice so that clinicians now typically order testing for a panel of multiple genes for most patients. Although this approach has streamlined the diagnostic odyssey, it has introduced several problems, as well, including difficulties in choosing the appropriate panel test for a given patient, assessing the significance of identified genetic variants (including variants of uncertain significance [VUS]), and understanding the disease risks and management associated with pathogenic variants in a given gene. Many laboratories offer testing for genes that have limited data supporting their associated cancer risks, which then leads to an inability to set management guidelines based on that gene. In addition, testing larger numbers of genes increases the likelihood of finding one or more VUS, which introduce their own management issues. Thus, although panel testing has certainly moved clinical practice forward in many ways, it has also raised its own set of problems that increase the complexity of genetic counseling and highlight the need for education of community practitioners on the complexities and nuances of this testing. Whenever possible, testing should be performed by, or in consultation with, cancer genetics professionals.
Submitted August 17, 2020; accepted for publication October 20, 2020.
Disclosures: The author has disclosed that he has no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.
Correspondence: Robert Pilarski, MS, LGC, MSW, Ambry Genetics, 1 Enterprise, Aliso Viejo, CA 92656. Email: email@example.com
MannelliM, CastellanoM, SchiaviF, . Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab2009;94:1541–1547.
MannelliM, CastellanoM, SchiaviF, . Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 2009;94:1541–1547.1922351610.1210/jc.2008-2419)| false
DalyMB, PalT, BerryMP, et al. NCCN Clinical Practice Guidelines in Oncology: NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2021. Accessed November 24, 2020. To view the most recent version, visit NCCN.org
WalshT, CasadeiS, CoatsKH, . Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA2006;295:1379–1388.
WalshT, LeeMK, CasadeiS, . Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 2010;107:12629–12633.10.1073/pnas.1007983107)| false
XuJ, LangeEM, LuL, . HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG). Hum Genet 2013;132:5–14.2306487310.1007/s00439-012-1229-4)| false
DesmondA, KurianAW, GabreeM, . Clinical actionability of multigene panel testing for hereditary breast and ovarian cancer risk assessment. JAMA Oncol 2015;1:943–951.10.1001/jamaoncol.2015.269026270727)| false
ChangJ, SengS, YooJ, . Clinical management of patients at risk for hereditary breast cancer with variants of uncertain significance in the era of multigene panel testing. Ann Surg Oncol2019;26:3389–3396.
ChangJ, SengS, YooJ, . Clinical management of patients at risk for hereditary breast cancer with variants of uncertain significance in the era of multigene panel testing. Ann Surg Oncol 2019;26:3389–3396.10.1245/s10434-019-07595-231342386)| false
TsaousisGN, PapadopoulouE, ApessosA, . Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer 2019;19:535.3115974710.1186/s12885-019-5756-4)| false
MightonC, ShickhS, UlerykE, . Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis [published online September 14, 2020]. Genet Med. doi: https://doi.org/10.1038/s41436-020-00957-2
MightonC, ShickhS, UlerykE, . Clinical and psychological outcomes of receiving a variant of uncertain significance from multigene panel testing or genomic sequencing: a systematic review and meta-analysis [published online September 14, 2020]. Genet Med. doi: https://doi.org/10.1038/s41436-020-00957-2)| false
Dominguez-ValentinM, NakkenS, TubeufH, . Results of multigene panel testing in familial cancer cases without genetic cause demonstrated by single gene testing. Sci Rep 2019;9:18555.10.1038/s41598-019-54517-z31811167)| false
AmendolaLM, JarvikGP, LeoMC, . Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am J Hum Genet 2016;99:247.10.1016/j.ajhg.2016.06.001)| false
LiuC, WangQS, WangYJ. The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:2051–2055.2290117010.7314/APJCP.2012.13.5.2051)| false
LiuC, WangY, WangQS, . The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2012;13:1355–1360.2279933110.7314/APJCP.2012.13.4.1355)| false
GronwaldJ, CybulskiC, PiesiakW, . Cancer risks in first-degree relatives of CHEK2 mutation carriers: effects of mutation type and cancer site in proband. Br J Cancer 2009;100:1508–1512.1940170410.1038/sj.bjc.6605038)| false
PeterlongoP, Chang-ClaudeJ, MoysichKB, . Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 2015;24:308–316.2533656110.1158/1055-9965.EPI-14-0532)| false
KuchenbaeckerKB, McGuffogL, BarrowdaleD, . Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 2017;109:djw302.10.1093/jnci/djw302)| false
van der PostRS, VogelaarIP, CarneiroF, . Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 2015;52:361–374.10.1136/jmedgenet-2015-103094)| false
PalT, LeeJH, BesharatA, . Modes of delivery of genetic testing services and the uptake of cancer risk management strategies in BRCA1 and BRCA2 carriers. Clin Genet 2014;85:49–53.10.1111/cge.1213023438721)| false
CohenSA, NixonDM. A collaborative approach to cancer risk assessment services using genetic counselor extenders in a multi-system community hospital. Breast Cancer Res Treat 2016;159:527–534.10.1007/s10549-016-3964-z)| false
PowellCB, LaurentC, CiaravinoG, . Streamlining genetic testing for women with ovarian cancer in a Northern California health care system. Gynecol Oncol 2020;159:221–228.10.1016/j.ygyno.2020.07.027)| false
ColomboN, HuangG, ScambiaG, . Evaluation of a streamlined oncologist-led brca mutation testing and counseling model for patients with ovarian cancer. J Clin Oncol 2018;36:1300–1307.10.1200/JCO.2017.76.278129558274)| false
OrmondKE, HallquistMLG, BuchananAH, . Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med2019;21:727–735.
OrmondKE, HallquistMLG, BuchananAH, . Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. Genet Med 2019;21:727–735.10.1038/s41436-018-0093-629976988)| false
BlazerKR, NehorayB, SolomonI, . Next-generation testing for cancer risk: perceptions, experiences, and needs among early adopters in community healthcare settings. Genet Test Mol Biomarkers2015;19:657–665.
BlazerKR, NehorayB, SolomonI, . Next-generation testing for cancer risk: perceptions, experiences, and needs among early adopters in community healthcare settings. Genet Test Mol Biomarkers 2015;19:657–665.2653962010.1089/gtmb.2015.0061)| false