The rapid evolution of hereditary cancer testing requires labs to thoughtfully design their test portfolios so that they evolve with our best understanding of current science, while meeting the practical needs of clinicians and patients. This design process is influenced by and balances many factors, including gene-disease validity (GDV), professional guidelines, insurance considerations and clinician preferences.

Gene-Disease Validity: The Foundation of Test Design

At the heart of any robust hereditary cancer test lies GDV. GDV evaluates the strength of evidence linking a gene with a particular disease. This is crucial for creating multigene panels with practical clinical value.

GDV scores help determine which genes should be included in panels. Most labs prioritize the inclusion of genes for which there is definitive evidence and consensus management guidelines to inform care. Likewise, labs should generally be wary of including genes with disputed evidence in association with cancer, as these genes increase the number of variants of uncertain significance (VUS) without adding clinical value, which may create confusion about their connection to disease.

But how should genes with moderate or limited GDV evidence be handled? There may or may not be consensus management guidelines to guide clinical care if a pathogenic variant is identified; therefore, clinicians and patients may have differing opinions on whether this information is desired. Specifically, genes with limited GDV evidence are still considered uncharacterized, and their inclusion on hereditary cancer tests leads to higher VUS rates without contributing to the diagnostic yield. Clinicians and patients who want the option of including limited evidence genes may hope for the benefit of learning more in the future, but these genes rarely become characterized in the hereditary cancer setting.¹ Labs should thoughtfully design their portfolios in ways that offer clarity to clinicians and patients with respect to these less clear-cut gene categories.

Professional Guidelines

A well-designed test provides clinical utility to help inform medical decisions. In this way, clinical guidelines, such as those from ClinGen or national consensus societies, also play a crucial role in test design. Labs rely on these guidelines to help maintain the consistency and clinical relevance of their tests.

When designing a menu, labs should include tests with a minimum number of genes known to be associated with the disease indication. This usually consists of genes with the highest GDV scores and penetrance. The next tier of tests typically includes characterized genes that have corresponding management recommendations but may have a moderate GDV score or lower penetrance. Labs can also choose to include genes with limited GDV evidence to allow for the broadest coverage, with the caveat that results from these genes are unlikely to be clinically actionable. One of the more complex challenges labs face is that guidelines may not always reflect the most current scientific evidence with respect to factors such as GDV. In these scenarios, labs must choose between prioritizing guidelines or their own internal frameworks. Ideally, the lab is consistent and transparent with respect to their approach.

Health Insurance Considerations

Insurance policies, particularly those from major payors like Medicare, can additionally impact test design. For instance, the Centers for Medicare and Medicaid services (CMS) develop local coverage determinations (LCD) that include criteria for policy eligibility. In some cases, they describe a minimum gene content by disease indication. Using breast cancer as an example, Medicare’s LCD indicates that the minimum gene content for a small, targeted breast cancer panel must include STK11. Some may argue that there is limited clinical utility in including STK11 in a targeted breast panel because individuals with STK11-associated Peutz-Jegher syndrome rarely have breast cancer as their sole presenting feature, but labs often try to be compliant with Medicare’s LCD when possible.

Whether a lab offers customizable multigene panels is also influenced by health insurance factors because there is a greater likelihood of medical necessity denial with custom panels given that a payor does not know what gene content to expect. Flexibility in test design is crucial for accommodating different clinical scenarios and patient needs; however, menu design should balance flexibility to customers with visibility to payors. This can be accomplished with test design features such as optional gene add-ons that provide a degree of customization without being a black box to payors.

Clinician Preferences and Test Ordering Trends

Last, clinician preferences change over time as scientific evidence, guidelines and familiarity with genetic data progress. For instance, there has been a notable shift from preference for small, disease-specific panels to broader, pan-cancer panels.

This is in part because accumulating evidence has shown that by focusing on a limited set of genes, important genetic information related to multiple cancer risks can be missed, especially given barriers to collecting accurate, complete family histories.² Pan-cancer panels address this by assessing a broader range of genes, offering a more comprehensive view of genetic risk.

Conclusion

Successfully designing hereditary cancer panels is a balancing act between gene-disease validity, clinical guidelines, evolving clinician preferences and payor considerations. Labs that can incorporate all of these factors will be positioned to offer tests that maximize clinical insights and minimize uncertainties.

Labs should continually refine their portfolios based on the latest scientific evidence, clinical needs, and real-world usage trends. By doing so, they not only enhance patient care but also contribute to the ongoing advancement of robust, evidence-based genetic testing.

1. Hollestelle A, Wasielewski M, Martens JW, Schutte M. Discovering moderate-risk breast cancer susceptibility genes. Curr. Opin. Genet. Dev. 2010;20(3):268-276. doi:10.1016/j.gde.2010.02.009.
2. LaDuca, H. et al. (2020). A clinical guide to hereditary cancer panel testing: Evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genetics in medicine: official journal of the American College of Medical Genetics, 22(2), 407–415. https://doi.org/10.1038/s41436-019-0633-8 

Carrie Horton, MS, CGC received her MS in genetic counseling from Arcadia University and practiced clinically as a cancer genetic counselor in Memphis, TN prior to joining Ambry Genetics 10 years ago. As a reporting genetic counselor at Ambry, she performed variant assessment, generated reports for oncology tests and curated clinical literature for report content. In her current role as sr. medical science liaison, she oversees studies focusing on the translational application and clinical engagement with Ambry's research. Horton's research interests include improving the clinical utility of and increasing access to genetic testing.