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BRCA Testing: When Negative Results Still Mean High Risk

by Kathy Steligo

For most people, receiving a negative test result for BRCA1/2 genetic mutations brings a huge sigh of relief. However, for people from families with a strong history of breast and ovarian cancer and no identified mutation, it may have an altogether different implication—they may be at increased risk despite a negative test result.

Genetic testing opened the door for predictive medicine, but it’s still a young science. We can only test for and identify mutations we know about. It’s like space exploration: we know how to navigate to Mars, but we haven’t a clue about finding as yet undiscovered planets in unknown solar systems—but we do suspect they’re out there somewhere. As researchers increase their understanding of breast and ovarian cancer, additional genetic risk factors will be identified and more comprehensive tests will find mutations that were previously missed.

In some cases where cancers “run in the family,” there are clear indications that hereditary factors are involved. Signs of hereditary cancers include:

  • Several relatives on the same side of the family with the same type of cancer
  • Family members who have cancer diagnosed at a young age (such as breast cancer before age 50)
  • Family members who have had more than one type of cancer
  • Uncommon cancers (such as male breast cancer)

The key to reliable genetic testing in these families is first testing a member who has had cancer, preferably the relative with the earliest age at diagnosis. If that relative is found to have a hereditary mutation, we can specifically identify the cause of the cancer occurring in that family. Other relatives who have not had cancer can then be tested to see if they have the mutation. Family members who test positive for the known mutation are at higher risk for cancer. Family members who test negative for the known mutation are true negatives with a cancer risk equal to people in the general population.

In some families it’s not possible to first test a cancer survivor. In this situation, testing a relative who has not had cancer is more likely to produce an inconclusive test, particularly if the result is negative. This may create a sense of false security—the person being tested may still carry a mutation we just don’t know how to find. The best way to assure correct interpretation of any genetic test is to consult with an expert in cancer genetics before and after testing.

Some families have a clear hereditary pattern for cancer, yet relatives consistently test negative for a known mutation. Because these families may have an undiscovered mutation, members are considered at high risk for cancer. As cancer genetic research continues, a future test may detect these unknown mutations.

Myriad Genetic Laboratories is the single source of BRCA1 and BRCA2 testing in the U.S. Myriad’s BRACAnalysis® test explores a portion of the BRCA genes where we would expect to find a mutation, although the current test cannot find all mutations along these genes. Additional hereditary syndromes found on genes other than BRCA1 or BRCA2 can also be linked to an increased risk for certain cancers. These mutations may require different testing procedures. Other genes, like CHEK2, for example, may increase the risk for breast cancer to a lesser degree than a BRCA mutation.

A large rearrangement is another type of BRCA1/2 gene mutation found in less than one percent of those tested. Since 2002, Myriad has been testing for the five most common large BRCA rearrangements. In August 2006, the lab added the BRACAnalysis Rearrangement Test® (BART) to find additional rearrangements. Myriad now automatically runs BART for individuals 1) from families with an inherited pattern of cancer but no identified mutation, and 2) whose family history meets certain criteria, and 3) whose initial testing produced a result of either “no mutation detected,” “genetic variant of uncertain significance,” or “genetic variant, favor polymorphism.” (See related article for explanation of these terms.) Individuals who meet these criteria and who tested negative for a BRCA mutation prior to August 2006 may benefit from this expanded test.


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