DNA analysis of the BRCA1 and BRCA2 genes

This information is about DNA analysis for people with a family history of breast and/or ovarian cancer. DNA is the 'genetic code' within our genes that helps control how the body's cells behave. This information should ideally be read alongside our information on cancer genetics.

You may also find it helpful to discuss things with the staff at your genetics clinic; or speak to one of our cancer support service nurses.

What is DNA analysis?

When a family with a strong history of breast and/or ovarian cancer has been offered genetic testing, the first step is usually a process called DNA sequencing, or a similar process whereby the DNA (genetic code) is analysed. This analysis involves examining the DNA of a family member who has already been diagnosed with breast or ovarian cancer. The family member, called the affected family member, provides a blood sample and their DNA is obtained from this.

BRCA1 and BRCA2 are genes that have been shown to play a role in hereditary breast and ovarian cancer (cancer that can be passed down through a family). Scientists are able to examine the DNA pattern (or sequence) of the affected family member’s BRCA1 and BRCA2 genes, and compare it to the 'normal' sequence in these genes. If a recognised change (or mutation) is found in the DNA sequence of one of the genes, this confirms that the family’s cancer is likely to be caused by a faulty gene. Only then can other family members be tested for this particular gene change.

Interpreting the results

It is important to understand that it is not always easy to interpret the results of DNA analysis. It is straightforward if the test reveals a mutation in the gene that is known to be associated with increased cancer risk, as described above. However, DNA analysis can sometimes produce a result that is not so clear cut and is therefore difficult to interpret.

Also, very occasionally, DNA analysis can miss a mutation or seem to find one that is not actually there. Thankfully, these situations are rare. Research studies show that the DNA tests usually used pick up 98 out of 100 of mutations, and may falsely find one in less than 1 in 100 tests.

When a mutation is found

There are several types of gene changes/mutations that DNA analysis can detect:

A mutation that is known to be linked to cancer risk

DNA analysis may reveal one of the known gene changes that is believed to increase a person’s risk of developing breast or ovarian cancer. If such a mutation is found in the affected family member, other family members can then be tested for the same mutation. This is called predictive testing.

Testing other family members takes less time because the scientists know what to look for, and don’t have to examine the DNA of the whole gene. This process of testing is called site specific analysis or single site analysis.

The result of a predictive test in a relative of the affected family member may be either positive or negative.

If the result of the predictive test is positive, this means that the family member has inherited the gene mutation and therefore has an increased risk of developing breast or ovarian cancer. They can also pass on the mutation to their children. But remember, a positive test does not mean that the person who carries the mutation will definitely get the cancer. It does, however, significantly increase the likelihood of that person developing cancer during their lifetime.

If the result of a predictive test is negative, the person has not inherited the gene mutation known to be associated with the cancer in their family. Their risk of developing breast or ovarian cancer is the same as that of the general population.

Possible mutations where the link with cancer is not so clear cut

Sometimes, DNA analysis reveals a gene change that is not so well known to scientists. This means it is difficult to say exactly how significant the gene mutation is to the family’s cancer risk. Testing other family members who also have breast or ovarian cancer (other affected family members, if there are any) may be helpful in this situation.

Broadly speaking, there are two types of mutation that, if found, could give an uncertain result. These are polymorphisms and unclassified variants.

Polymorphisms A polymorphism is a change in the BRCA1 and BRCA2 genes, which has been found in the general population, and is not thought to be linked to increased cancer risk. Polymorphisms are thought to be normal variations of the gene.

Unclassified variants An unclassified variant is an alteration in the BRCA1 and BRCA2 gene that is of ‘uncertain significance’. This means that scientists do not currently know if this alteration will have a significant effect on cancer risk. In this situation, the significance may become clearer by testing other members of your family if they have developed cancer. You would then be informed if the significance of the gene variant becomes clear.

When no mutation is found

In many cases of DNA analysis, no mutation is found in any of the genes known to be involved in hereditary breast/ovarian cancer, even if there is a strong family history. Overall, mutations are only found in about 10 to 20 of every 100 tests.

However, this does not mean that the family in question is not at an increased risk. In fact, if there is a very strong family history of breast or ovarian cancer, doctors assume that the members of this family are at increased risk of that cancer type, even if the laboratory cannot find a specific gene mutation.

There are several possible reasons for a test not showing a mutation:

• The test might have missed the mutation
• The entire gene sequence may not have been tested (you should be told what percentage of the gene is to be tested). So the mutation in a specific family could be on a part of the gene that the laboratory didn’t examine. In the future, better testing facilities will be available that will enable all NHS laboratories to analyse the DNA of the whole gene
• It is possible that there is a gene change/mutation present in a family with a strong history of breast/ovarian cancer, but in a gene that has not yet been identified
• The cancer in the family, or person, isn’t actually due to an inherited gene change/mutation, and the clustering of cases of cancer has occurred by chance.

Advantages of DNA analysis

DNA analysis can provide important information for families who have a very strong history of breast or ovarian cancer. It enables patients and relatives to make important life decisions according to the knowledge that they have gained. Also, the affected family member may take some comfort in the fact that they have done all they can to find out about their family’s possible risk.

Disadvantages of DNA analysis

Unfortunately, genetic testing does not remove uncertainty for everyone. For example, finding a mutation of unknown significance, or even no mutation in the affected family member, can leave people no wiser regarding their possible risk. Going through the process of genetic testing and dealing with the uncertainty of it all can be a stressful experience.

Support for you and your family

Scientists are only just beginning to understand the role of genetics in cancer. This can be very helpful, but does not yet give us all the answers. Scientific developments and/or future improvements in testing methods may help to clarify your test result at a later date. So, it is important to stay in touch with your genetics clinic in case of new technologies or information regarding your result.

The staff at your genetics clinic know your situation in detail; they can support you and your family through the process of genetic testing, and can help you to understand what the results of the test might mean for you.

Insurance

Some people are worried that once they have had a genetic test they might be subject to discrimination – by insurance companies, for example. However, there is a voluntary agreement (called the Concordat and Moratorium) between the Department of Health and the Association of British Insurers (ABI).

Under the terms of the Moratorium you can apply for up to £500,000 of life insurance, or £300,000 of critical illness insurance, without having to tell the insurer the results of any predictive genetic test. See other questions about genetic tests for more information on this.

References

This section has been compiled using information from a number of reliable sources, including:

• GeneticHealth, www.genetichealth.com, 15.04.05

For further references, please see general bibliography.