Finding out that you have inherited a mutation in BRCA1 or BRCA2 — the two most common genes known to be associated with breast and ovarian cancer — provides valuable information that can help you reduce your risk for these diseases, or catch them early enough to allow successful treatment.

Genetic testing for mutations in these genes is complex because there are hundreds of possible mutations to look for. Also, even if a mutation is found it does not mean that a person will develop breast cancer – only that they have a higher lifetime risk of the disease.

Testing BRCA1 and BRCA2 Is Complex
Who Should Consider DNA Testing?
What testing Can Tell You?
Where Should Testing Begin?
Available Tests
The Final Decision: To Test or Not to Test?

Testing BRCA1 and BRCA2 Is Complex

In the world of DNA testing, it's ideal to have a relatively small gene that has a limited number of mutations associated with a single disease. In other words, the smaller the area to be analyzed and the fewer mutations to be identified, the easier the testing process.

Unfortunately, the two genes known to predispose to breast and ovarian cancer — BRCA 1 and BRCA2 — do not fit this scenario.

BRCA1 and BRCA2 each contain more than 16,500 base pairs (units of DNA), making them eight times larger than the average gene. Furthermore, there are hundreds and hundreds of identified mutations in each of these genes that can increase a person's risk for breast cancer.

Many of these mutations are unique — they have only been identified in individual families. The exceptions are a handful of mutations that researchers believe are caused by the founder effect. Founder mutations are common in populations that historically were isolated or homogenous, such as people of Ashkenazi Jewish descent or people living in Iceland, Denmark, or the Netherlands.

More on: Risk for People of Ashkenazi Jewish Ancestry

Who Should Consider DNA Testing?

Physicians and scientists do not consider genetic testing for hereditary breast and ovarian cancer (BRCA1 and BRCA2) appropriate for the average person. They consider it appropriate for women who have a high risk for these cancers based on a personal and/or family history.

This is for a number of reasons: First and foremost, only 5 to 10 percent of all breast and ovarian cancers are caused by mutations in the BRCA genes. Also, having a BRCA mutation does not mean that a person will automatically develop cancer. Lastly, there is no 100 percent-effective way to prevent breast or ovarian cancer should a mutation be discovered.

Who Is High Risk?

People with a personal history of at least one of the following:

• Invasive breast cancer before 50 years
• Ovarian cancer at any age
• Both invasive breast cancer and ovarian cancer at any age
• Male breast cancer at any age

People with invasive breast cancer or ovarian cancer who have one of the following:

• One or more first-degree relatives (mother, father, sister, daughter) or second-degree relatives (aunt, uncle, grandmother, niece, granddaughter) with invasive breast cancer diagnosed before 50
• One or more first- or second-degree relatives with ovarian cancer
• One or more first- or second-degree relatives with male breast cancer
• Clinically unaffected patients with a family member with a known BRCA1 or BRCA2 mutation
• Individuals of Ashkenazi Jewish (Eastern European) ancestry with invasive breast or ovarian cancer at any age, or meeting any of the above criteria.

What Can Testing Tell You?

Genetic testing can give important information to people at high risk for hereditary breast or ovarian cancer.

For example, if a woman tests negative for a mutation that is known to run in her family or ethnic group, she can have the relief of knowing that she is at no greater risk of developing these cancers than the average woman. As a result, she can follow the screening guidelines recommended for the general population.

If a woman at high risk tests positive for a BRCA mutation, there are a numbers of options she can pursue to lower her risk for the disease. These options include more aggressive screening guidelines, taking preventive medications, having risk-reducing surgery, or altering her lifestyle to reduce her risk.

For people who have a strong family history of breast or ovarian cancer but do not know the mutation involved, genetic testing offers less conclusive results. If doctors do not find a mutation in the family, these women should still follow more aggressive screening strategies based upon their high-risk family history.

Where Testing Should Begin?

While you may meet the high-risk criteria outlined above, you might not be your family's best candidate for genetic testing. Why?

Testing should begin with the family member who is most likely to have a cancer-related genetic mutation — and that generally means someone who's already been diagnosed with breast or ovarian cancer. Testing this person presents the best chance of identifying a genetic mutation.

For most people, this means running a full sequence test to examine the entire BRCA1 and BRCA2 genes to look for a mutation.

If a mutation is found, it is considered to be the explanation for your family's hereditary cancer. As a result, you and other family members can be tested to see if you carry this specific mutation.

This makes subsequent testing easier and cheaper, since you can be tested for one mutation rather doing a full sequence of both BRCA genes.

Testing should begin with a family member who has been diagnosed with breast or ovarian cancer.

Available Tests

There are three types of genetic tests for breast and ovarian cancer risk: DNA sequencing, multisite analysis, and single site analysis. All three tests require a blood sample.

DNA Sequencing

This test is considered "gold standard" because it is the most comprehensive method of testing the BRCA1 and BRCA2 genes. It maps the complete sequence of the genes and detects all changes in the genes — regardless of whether such changes affect the gene's function or the protein it produces.

DNA sequencing can sometimes produce inconclusive or uninterpretable results. This is because it will pick up harmless variations in the genetic code, or genetic changes whose link to breast cancer is not known. (These types of changes are known as variants of unknown clinical significance.)

Also, even though DNA sequencing is the most comprehensive form of testing available today, researchers estimate that it still overlooks 10 to 15 percent of the mutations that can occur within these two genes. For this reason, you may still carry a mutation in BRCA1 or BRCA2 even if sequencing doesn't detect a mutation.

More on: Testing With an Unknown Mutation in the Family

This test looks for three specific mutations, often called the founder mutations, that researchers believe account for 80 to 90 percent of the inherited breast and ovarian cancers in people of Eastern European Ashkenazi Jewish descent. These mutations are called:*

• BRCA1: 187delAG
• BRCA1: 5385insC
• BRCA2: 6174delT

Because this test is so specific — that is, it's designed to detect only these mutations — it gives conclusive results. The test either turns up one of these mutations (a positive result), or it does not (a negative result). However, a negative test result does not necessarily mean that you do not have a mutation in BRCA1 or BRCA2. It simply means that you do not have one of these three mutations.

For this reason, some people who get a negative result from this test decide to follow up with DNA sequencing to identify any other mutations in the BRCA1 or BRCA2 genes. If you have you have a family history of the disease, but mutisite analysis and DNA sequencing fail to turn up a mutation, then the mutation in your family may be one that cannot be detected or is located in a different, unidentified gene.

More on: Risk in Ashkenazi Jewish People
More on: Genetic Testing in Ashkenazi Jewish People

Single Site Analysis

This test can only be performed for people who come from families in which someone has already tested positive for a BRCA mutation. Since the cancer-causing mutation has already been identified, the lab can simply look for that one specific mutation.

Like multisite analysis, this test is specific enough to give you a conclusive result: Either you have the mutation that runs in your family or you don't.

More on: Testing With a Known Mutation in the Family

The Final Decision: To Test or Not to Test?

There are many factors to weigh — some scientific, some emotional — when deciding whether or not to get genetic testing.

Ultimately, the decision is a personal one, and no one can tell you with absolute certainty which choice is right for you. If you have questions about your personal or family risk, DNA Direct's genetics experts can walk you through the issues involved, so that you can make the best choice for yourself and your family.

If you would like to explore whether testing is right for you or your family, you can call DNA Direct to speak with a genetic expert: 1-877-646-0222.