Hereditary Cancer Panels

Multi-gene hereditary cancer panels simultaneously test for variants in multiple genes that have been associated with increased cancer risk. Increasingly, providers use multi-gene panel as a first tier test as opposed to testing for single genes or testing in a stepwise manner, unless there is a known familial variant or a pattern of disease that clearly suggests a specific hereditary syndrome. Both cancer-specific (e.g., breast cancer, gastrointestinal cancer) and pan-cancer panels are available.  

Benefits of Expanded Testing: Higher Detection Rate

  • may identify pathogenic variants in rarer genes in individuals who would test negative for common hereditary syndromes
  • the clinical presentations of various hereditary cancer syndromes can overlap, so allows for simultaneous evaluation of multiple genes or syndromes 
  • can identify pathogenic variants in individuals who do not meet classic clinical criteria for hereditary syndromes

While no test can rule out hereditary cancer with 100% certainty, a negative result on a multi-gene panel is more reassuring than a negative result for one or a few genes.

Limitations and Risks of Expanded Testing: Uncertain Findings

The sensitivity of expanded testing must be weighed against the risk for uncertain findings, which increase with the number of genes included on the test.

Variants of Uncertain Significance

An “uncertain” variant, also called variant of uncertain significance, or VUS, is one that lacks sufficient evidence to determine whether it increases cancer risks. A variant is classified as uncertain when it is

  • novel or rare, or
  • well-described but associated with conflicting evidence about cancer risk.

Uncertain results should not be used for medical decision-making or testing of at-risk relatives.

Limited Evidence for Moderate Risk Genes

Multi-gene panels may include genes with moderate contribution to risk, which may be difficult to use for clinical decision-making. Some considerations for these moderate risk genes include:

  • may be no more useful for estimating lifetime cancer risks than family history alone
  • management guidelines may be lacking for individuals with variants in some of these genes, which can result in uncertainty about cancer risk management for the patient

Secondary Findings

Multi-gene panels may identify secondary findings, results that are clinically significant for the patient and/or family members, but unrelated to the reason for testing.

This information could be seen as both a benefit and a risk, as there are potential for psychological implications for the patient but can provide guidance for screening that might not otherwise have been recommended.

Role of Cost, Billing, and Reimbursement

Multi-gene panels are often more cost effective than ordering stepwise single gene tests separately. The cost for the same or similar tests may also vary between laboratories.  Some labs offer very reasonable patient pay options for panels.

Guidelines regarding the use of multi-gene panels are evolving, and changing insurance billing and reimbursement practices may complicate testing strategy. Some patients can access multi-gene panels as a first tier test, but paradoxically do not have coverage for an “update” to a multi-gene panel if single gene testing has already been performed. Some labs offer client-initiated panel testing with self-pay options if the patient does not meet coverage criteria.

Shared Decision-Making

Informed decision-making can facilitate better patient understanding of the benefits, risk and limitations of multi-gene panel testing. The National Comprehensive Cancer Network details the benefits and limitations of multi-gene testing and recommends this discussion take place during pretest counseling.

As our understanding of the genetic contribution to cancer improves, the genes included in expanded panels will change. The number of uncertain findings will also decrease as more is learned about the functional effects of rare variants in cancer risk genes. Cost, analytic performance and scope are also likely to change. Due to the rapidly evolving nature of these issues, consider consulting with a genetic expert to inform testing strategy.


National Comprehensive Cancer Network: Genetic/Familial High Risk Assessment: Breast, Ovarian and Pancreatic (1.2020); Genetic/Familial High Risk Assessment: Colorectal (3.2019). (Free registration required for access).


Updated May 2020