Hereditary Cancer Predisposition Testing
Cancer is a complex, multi-factorial disease due to both inherited genetic and environmental factors. About 5-10% of cancers are familial, with underlying inherited genetic predisposition suspected. During the past several decades, researchers have uncovered both common genetic variants conferring small increased or decreased risk of certain cancers, as well as rare genetic variants increasing a person's risk several fold.
Genetic testing has changed dramatically in the past few years due to technological advances and changes in the legal policy landscape. The result is that dozens of laboratories now offer hereditary cancer tests for several cancer types. These tests are growing in terms of the number of genes evaluated as well, from single genes to panels of a dozen or more genes.
Navigating the landscape of hereditary cancer testing can be overwhelming. Health care providers may have several questions, including: whether their patient is a candidate for testing; how to select the right test; how to interpret results; and how much the tests costs and whether it is covered by insurance.
Is my patient a candidate for hereditary cancer testing?
One of the telltale signs of hereditary cancer is a family history, especially if the cancer occurs in multiple generations, and occurs at an early age of onset. Because our understanding of the underlying genetic predisposition to cancer is incomplete, family history remains a strong and important risk factor.
Even in the absence of family history, there may be telltale signs of hereditary cancer, including:
• Multiple independent different types of cancer in same person
• Bilateral cancer (i.e. both kidneys or both breasts)
• Unusual cases (e.g. male breast cancer)
A list of rare benign and malignant tumors and the criteria that warrant assessment for cancer predisposition can be found in a 2015 guideline from the ACMG Referral Indications for Cancer Predisposition Testing.
Learn more about genetic testing for hereditary cancer syndromes by visiting this site from the NIH.
How do I select the right test for my patient?
Selecting the right test for your patient requires an understanding of what tests are available and how they differ from each other. NextGxDx is a resource hub for laboratories offering genetic testing.
Searching for hereditary breast cancer, for example, will bring up a list of laboratories offering the test as well as a list of the genes on their panels (with the option to compare gene lists across companies).
Panels vary with respect to the numbers of genes. Larger gene panels are not always better. Smaller panels usually include just those genes with the highest penetrance and strongest supporting evidence. Larger panels may include additional genes that are less well-validated or for which the penetrance is unknown.
Turn around time, cost, quality and customer support are additional considerations.
How do I interpret the results from my patient's hereditary cancer test?
Sequencing technologies used in most laboratory tests will likely identify one or more genetic variants in each of the genes tested in every patient. However, not all of these variants are pathogenic. To distinguish the pathogenic from benign variants, evidence from various sources is weighed. This evidence may include computational, functional and clinical elements, which are evaluated by trained geneticists.
Classification of variants
Most laboratories present their assessment of genetic variants on a probabilistic scale modeled on the American College of Medical Genetics (ACMG) framework, which classifies variants as Pathogenic, Likely Pathogenic, Unknown Significance, Likely Benign and Benign. Different labs may use different terminology, or have more or fewer categories describing their variant classes. A laboratory might not report all variants found in the genes evaluated, maybe just the Pathogenic or Likely Pathogenic variants.
Pathogenicity vs penetrance
Pathogenicity measures how likely the gene variant is going to affect the protein and subsequently impact the disease. One should also be aware that the different genes tested may have different implications in terms of disease risk. Some genes confer a higher risk of cancer to patients than others. In other words, a pathogenic variant in one gene may confer a different risk of cancer than a pathogenic variant in another gene on that panel. These risk or 'penetrance' estimates should be provided in your report.
How much do hereditary cancer tests cost and are they reimbursed?
Hereditary cancer tests typically cost from hundreds to thousands of dollars. A recent study out of UCSF found the average price for a BRCA1/2 panel to be around $2000, and the average price for larger breast cancer gene panels to be about $3500. The most economical commercial option currently available is a hereditary breast cancer panel offered from Color Genomics for $249.
Reimbursement of cancer genetic panels varies by insurance company. The study by UCSF found that while most insurance companies (76%) have coverage policies around cancer gene panels, most are considered investigational/experimental, offering either no coverage or coverage only if all components are medically necessary.
Where can I learn more?
To learn more about specific tests, their cost and reimbursement, contact testing companies directly. You can also contact Duke's Hereditary Cancer Services where you can speak with a genetic counselor about choosing the right test for your patient.