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FORCE Publications

New Tools Help with Uncertain or Negative BRCA Results

by Lisa Rezende, PhD and Sue Friedman

BRCA test results sometimes don't provide clear answers about cancer risk. Several types of BRCA tests can produce varying results, which have different health implications. This is why genetic counseling before and after genetic testing is so important.

True Negative

When a family member tests positive for a BRCA mutation, that particular mutation is known to be the cause of cancer in that family, and other blood relatives can then be tested for the same mutation. Anyone who tests negative for a known mutation in their family is considered a "true negative." Their risk for cancer is similar to the risk for cancer in an average person (see our related article Weighing the Evidence in this issue).

Uninformative Negative

Mutations in BRCA1 and BRCA2 account for about half of all hereditary breast and ovarian cancers; many families who may experience a lot of cancer have no known mutation. In families who have multiple diagnoses of breast and/or ovarian cancer, when all members test negative for a BRCA mutation, their results are categorized as "uninformative negative" because the negative test does not indicate anything about family members' cancer risk.

In addition to BRCA1 and BRCA2, mutations in other genes can cause hereditary breast and ovarian cancers. Some, such as the genes that cause Lynch Syndrome, are part of known hereditary cancer syndromes. Others may be caused by mutations in one or more genes that somewhat increase cancer risk, and result in higher risk when inherited together.

Variants of Uncertain Significance

Some BRCA test results indicate a "variant of uncertain significance" (VUS). It is normal to have variations in genes, and some changes do not affect how the gene functions. Gene changes that cause a particular eye color, for example, do not affect vision. Similarly some changes in the BRCA genes can cause the gene to stop working, while other changes may be harmless variations that don't affect cancer risk. New tools and databases are being developed to help families with a BRCA VUS to better understand their risk of cancer. (See related article "Free the Data" in this issue.)

Improvements in BRCA Testing

Since the availability of BRCA testing, the genetic testing technology has improved, and will likely continue to become more precise in the future. In the past, some tests failed to identify certain BRCA1 and BRCA2 mutations known as 'rearrangements' as well as other mutations. Some families that previously tested as "uninformative negative" for BRCA in the past may benefit from expanded panels that look for newly identified BRCA mutations.

Testing Multiple Genes to Assess Risk

If your family has a strong history of breast or ovarian cancer but has no known BRCA mutation, you have other testing options. A genetics expert can help you determine whether additional tests for specific genes, or new 'multiplex panel testing' that scans several genes may provide additional information after a negative BRCA test.

Mutations in other genes can cause inherited breast and ovarian cancers, including PTEN (Cowden Syndrome), STK11 (Peutz-Jeghers Syndrome), TP53 (Li-Fraumeni Syndrome), CDH1 (hereditary diffuse gastric cancer), and a host of genes known to cause Lynch Syndrome.

Some new panel tests include mutations in dozens of genes that are not associated with a specific cancer syndrome but still may put an individual at a higher risk of cancer than the average person. Such panels look for mutations in genes such as PALB2, CHEK2, and ATM that are known to increase cancer risk. Not enough research has been conducted for some genes in these panels to identify that risk, and we have even less research on the best ways to manage risk for cancer in people who have mutations. Results from these tests are complicated, and more research is needed to understand how a mutation in one of these genes, or a combination of mutations in several of these genes might affect cancer risk, and in whom. Genetics experts can help patients to understand how their unique genetic profile affects their cancer risk and the steps they can take to lower their risk of developing cancer and increase their chances of survival.

FORCE is dedicated to helping individuals and families who face hereditary breast and ovarian cancer. We are developing new resources to help families who test positive for mutations in genes other than BRCA1 or BRCA2 to understand their risk.

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