Genetic Testing & Counseling

What are genes?

Genes are the instruction manuals within in all of our cells. Genes are made up of DNA, which act as letters that spell a chemical code. Through the chemical code the body receives messages that control every bodily function. Most body functions, such as digestion, are complicated and involve not just one, but many genes. Certain genes may produce brown hair while other genes send messages for blonde hair. When a gene is not working properly, it is said to be altered or mutated. A gene mutation may disrupt a normal body function. If certain genes, like BRCA1 and BRCA2 , have errors or mutations, they stop working properly and the cells may not get the proper instructions about when to grow and divide. Cells can then grow more quickly without the normal genetic controls, and form a tumor.

What is cancer and why does it happen?

The human body is made of millions of individual cells.  Cancer  is a condition where certain cells in the body are no longer growing and dividing normally. Cancer cells may grow too quickly and form a lump, or a  tumor . When cancer cells are seen under a microscope, they show certain distinct features. A pathologist, a physician specializing in the study of cells, can determine if they are cancerous. If cancer is present, a tumor is malignant. If cancer is not present, a tumor is considered benign.

What is the difference between sporadic and hereditary cancers?

Most people develop cancer sporadically due to a combination of many factors, such as environment, lifestyle and random cell damage. It takes many years for these factors to accumulate over a person’s life, which is why most people with sporadic cancers are over the age of 50.

Individuals with hereditary forms of cancer risk are born with one mutated copy of a cancer risk gene in every cell of the body. Inheriting a mutation is a gene controlling normal cell growth causes increased cancer risk. However, these cancer risk gene mutations do not guarantee cancer will develop. Inheriting a mutation in a cancer risk gene, like BRCA1 or BRCA2, means your risk is higher than someone who was not born with a mutation.

What are BRCA1 and BRCA2?

BRCA1 and BRCA2 are just two of about 20,000 genes inside of every cell of your body. They are tumor suppressor genes, which means they play a role in controlling or preventing cancer. Both men and women have BRCA1 and BRCA2 genes. When there is a mutation in a BRCA1 or BRCA2 gene, an individual has increased cancer risks. They can also pass the mutation on to their children who will then have increased cancer risks in adulthood.

How can cancer risk run in a family?

Genes are inherited from your parents. We all have two copies of each gene – one copy is inherited from our mother and one copy from our father. Most mutations in cancer risk genes, like BRCA1 and BRCA2, are called dominant mutations. This is because having a mutation in only one copy of the gene is enough to increase cancer risk.

A parent who has a mutation in a cancer risk gene has a 50% chance of passing it on to each of his/her children, and a 50% chance of passing on the normal copy of the gene. Men, as well as women, can inherit and pass on a mutation in a cancer risk gene to either a son or a daughter.

Are breast and ovarian cancer inherited?

Only about 5-10% of breast cancers and 10-15% of ovarian cancers are strongly related to mutations in single high cancer risk genes. Breast cancer is a common disease, affecting about 13%, or 1 in 8 women in the United States. Ovarian cancer is less common, affecting about 1-2%, or 1 in 70 women in this country. While most women who develop breast or ovarian cancer have sporadic (random, non-hereditary) cancers, a small number develop cancer because they inherited a significant risk of developing these cancers due to a mutation in a cancer risk gene.

Are mutations in BRCA1 and BRCA2 the only ones that increase cancer risk?

While it is known that mutations in BRCA1 and BRCA2 can increase cancer risk, it is also known that there are other genes that impact a person's cancer risks. Genetic testing of genes other than BRCA1 and BRCA2 may be suggested if there is a significant chance of finding information that will impact medical care. It is likely there are more undiscovered genes that increase breast or ovarian cancer risk.

Better testing technologies are allowing researchers to take an in depth look at the entire DNA sequence. Through this "whole genome" approach more and more cancer susceptibility genes will be identified. It will take time to determine if these genes increase risk enough to impact medical care.

Are BRCA1 and BRCA2 mutations common? Are Ashkenazi Jewish people more likely to have them?

Inherited mutations in the genes BRCA1 and BRCA2 are rare. Only about 1 in 200 individuals have a mutation. However, these gene mutations are more common in certain ethnic groups. For example, men and women of Eastern or Central European Jewish descent (Ashkenazi Jewish) have a 1 in 40 chance of having a BRCA1 or BRCA2 mutation.

What is PALB2 and what does it mean for me?

Like BRCA1 and BRCA2, PALB2 is one of the body's roughly 20,000 genes. The PALB2 gene produces proteins that work with the BRCA2  gene. Mutations can occur in the PALB2 gene but are quite rare and are found in 1% of women with breast cancer.

Individuals with a PALB2 mutation have an increased risk of breast cancer. Current research has shown that PALB2 mutations increase a woman's risk of breast cancer to 35% by age 70 and can be higher depending on her family history. PALB2 mutations also appear to increase the risk of male breast cancer and pancreatic cancer; although the exact lifetime risks are unknown. Research is ongoing to determine if PALB2 mutations increase the risk for other cancers.

If you have tested positive for a BRCA1/2 mutation and are being followed under a personalized cancer risk management plan, it is highly unlikely that testing for PALB2 would be helpful to you because your hereditary risk is already known.

If you've tested negative for a BRCA1/2 mutation, please speak to your genetic counselor about whether testing for additional genes that increase cancer risk makes sense for you in the context of your personal and family history.

Genetics is a constantly evolving field. Questions about testing for additional genes that may increase cancer risk should be directed to your genetic provider.

What is cancer risk evaluation?

Cancer risk evaluation involves meeting with a genetics specialist to estimate your personal risk for different cancers by reviewing your personal and family history of cancer, and sometimes undergoing genetic testing. Knowing about the presence of increased risk for cancer can provide important, sometimes life-saving options such as increased cancer screening, prophylactic surgeries, and medications.

Who should consider genetic testing?

A complete personal and family history, including at least three generations of relatives on both you mother and father’s side of the family, should be examined to determine if a mutation is present in a high risk cancer gene. Consider genetic risk evaluation if you or a family member has had*:

• Breast cancer at age 65 or younger
• Triple negative breast cancer at any age
• Ovarian or fallopian tube cancer at any age
• More than one breast cancer diagnosis
• Male breast cancer
• Pancreatic cancer
• Metastatic prostate cancer
• Anyone of Ashkenazi Jewish ancestry
• A known mutation in a cancer risk gene
• Breast, ovarian, pancreatic, or high grade prostate cancer diagnosed in multiple individuals on the same side of the family

* A genetics specialist can help to determine if your personal and/or family history meets these or other criteria.

How do I find a genetic counselor in my area?

To be seen by a genetic counselor at Penn Medicine, contact the MacDonald Cancer Risk Evaluation Center at 215-349-9093.

You can also search the National Society of Genetic Counselors’ Find a Genetic Counselor tool  or contact your local cancer center. Genetic counselors who perform BRCA testing are often a part of the breast group of academic medical centers or cancer centers. 

How is genetic testing done?

Genetic testing involves the collection of DNA typically through a blood test, or a saliva collection kit. DNA, the genetic material which contains all the genes, is isolated from the cells and studied for the presence or absence of inherited mutations in specific genes.You can think of genetic testing as a "spell-checking process," where the letters of the genetic code in specific genes are studied for misspellings. Some misspellings are harmful and are called mutations.

What is the difference between germline and somatic genetic testing?

Genetic testing done on normal, non-tumor cells (usually blood or saliva) to find inherited mutations in genes, such as BRCA1 and BRCA2, is known as germline testing. Germline testing helps to identify mutations that are present at birth and/or passed down from a parent. Individuals who carry a germline mutation have an increased risk of developing cancer over their lifetime.

Somatic testing looks for mutations within a specific tumor, and has been developed to learn about the genetic makeup of a person’s cancer. By knowing the gene mutations that are making the cancer grow, an oncologist can potentially target those mutations to treat a cancer. The goal of somatic testing is to provide personalized treatment for a person’s specific cancer.

While germline and somatic testing are designed to provide different information, in certain individuals, somatic genetic testing may find a mutation that could possibly also be present as a germline mutation. The results of somatic testing alone cannot determine whether the mutation exists in the normal cells or only in the tumor and germline testing would be the next step.

What are the benefits and limitations of genetic testing?

Some benefits of genetic testing include:

• The opportunity to design a personalized cancer screening program, tailored to individual risk.
• Development of a treatment plan that can reduce cancer risk in individuals who test positive. This may include having to make difficult medical decisions, like whether or not to have prophylactic mastectomy (surgical removal of the breasts) or oophorectomy (surgical removal of the ovaries).
• Understanding the source of cancer risk in the family.
• Making cancer risk information available for other family members, including children once they become adults.
• Improved ability to cope with cancer risk, since the risk could be better defined and understood through genetic testing.
• In families with a known high-risk gene mutation, some people will learn they did not inherit a gene mutation in the family and are not at high risk for cancer in spite of their family history of cancer.

Some limitations of genetic testing include:

• There may be a mutation in an untested or undiscovered gene. Additional genetic testing may be recommended in the future.
• The possibility of finding a variant of uncertain significance for which cancer risk is not currently known.
• Results of testing may cause someone to experience worry, anxiety, or other emotional distress.
• Testing can be expensive, and while most insurances cover the cost of testing when indicated, some insurances may not. Information about insurance coverage can be obtained to help make genetic testing decisions.
• The state-of-the-art genetic testing may not find all gene mutations. Some mutations may not be detectable using the current technology, but the chance of an undetectable mutation is low.

Who in my family should get genetic testing? Why not me?

It is suggested that testing in the family start with someone who has had an early onset (before age 50) of breast, ovarian or male breast cancer. This is because that person is most likely to have an inherited mutation, if a detectable mutation exists in the family. However, this relative with cancer may either be unavailable or unwilling to be tested. In this situation, testing can still be performed on someone who is not affected with cancer. Through the genetic counseling process, you will understand what testing strategy will be most informative for your family.

How and when do I decide to get genetic testing?

Deciding whether or not to have genetic testing is a personal decision. Meeting with a genetic counselor may help you to understand if you are a candidate for genetic testing and what that information would mean for you and your family. Meeting with a genetic counselor does not mean you must undergo testing.

When to have genetic testing should also be considered. Women often undergo testing around age 25 because this is the age when medical management would change. Men often undergo testing between ages 35-40 because this is when medical management would change. Individuals may undergo testing at different times should they be interested in using reproductive technologies to avoid passing down a hereditary gene mutation. Children are not candidates for BRCA testing.

Will I only be tested for mutations in BRCA1 and BRCA2?

While it is known that mutations in the BRCA1 and BRCA2 genes are the main causes of inherited breast and ovarian cancer risk, it is also known that there are other genes that impact a person’s cancer risk. In the past, genetic testing for cancer predisposition was done by looking at one or two genes, often BRCA1 or BRCA2, based on the pattern of cancers in a family. Recently, gene panel tests have been developed, which look for mutation in many genes at the same time in a single test. Your genetics provider can discuss the pros and cons or gene panel test and whether they are appropriate for you and your family.

Should I talk to my other family members about genetic testing?

Learning about the presence of an inherited mutation that increases risk for cancer can also affect other family members, and possibly even family relationships. Other relatives could learn more about their cancer risk through testing a parent, brother, sister or cousin, and this information may or may not be welcome. While we strongly encourage people to share genetic testing information with relatives, ultimately each family member will need to choose whether or not to be tested.

Should children be tested for mutations in BRCA1 and BRCA2?

Currently, children are not candidates for BRCA testing since there is no known cancer risk or medical intervention that takes place during childhood, and testing may be psychologically difficult for children.

In addition, all individuals should be given the chance to make their own decision about testing, and the vast majority of children are not prepared to do so independently.

What are the possible results of the BRCA test?

The results can be:

• Positive -  a mutation is detected that increases cancer risk.
• Negative -  no mutation is detected. The interpretation of this result is crucial for understanding whether increased cancer risk is present or not. You can still have increased cancer risk with a negative BRCA result.

Variant of Uncertain Significance   - a gene change is detected but it is currently unknown whether the change increases cancer risk or not.

What does a positive result mean?

A positive genetic test result means that a mutation was detected in either the BRCA1 or BRCA2 gene, or another high-risk cancer gene, that increases your risk of certain cancers. The printed result will indicate which gene has a mutation and the specific mutation. This result means that you have increased cancer risks and need to be managed differently. Once a cancer risk gene mutation has been found in a family, relatives may wish to consider genetic testing to better understand their risk for cancer.

What happens if I have a Variant of Uncertain Significance result?

A variant of uncertain significance (VUS) is a change in the gene, but it is currently unknown whether the gene change increases cancer risk or not. A gene is “spelled” with DNA letters that make up a code. A VUS is a difference in how the gene is spelled, but it is currently unclear whether it is a harmful mutation (positive result) that increases cancer risk or whether the chance is a harmless difference that has no impact on cancer risk (negative result). We do not use a VUS result to recommend changes to medical care, since it is unknown whether it is causing elevated cancer risk. A VUS may be reclassified at a later date when more is known about its impact on cancer risk.

What does a negative result mean?

Negative BRCA Test Result: When A Family Mutation is Known

When a mutation in a high-risk cancer gene like BRCA1 or BRCA2 is found, then the source of cancer risk in a family is known. If relatives in the family are tested for the known mutation and receive a negative test result, then they generally have an average risk for developing cancer. This is considered a “true negative” result.

Negative BRCA Results: When a Family Mutation is Unknown

A negative genetic test result means no mutations were detected. There are a few explanations as to why someone may receive a negative result:

• The cancer in the family is not due to a mutation in a single cancer gene. In most families, multiple genetic factors, along with environmental and lifestyle factors, determine cancer risk.
• There is an undetectable mutation in the cancer gene(s) tested.
• The cancer in the family may be associated with a cancer gene that was not tested or has yet to be discovered.

When no one in the family has been found to have a detectable cancer gene mutation, negative test results need to be interpreted with caution. Unless there is a known mutation in the family, a person with a negative genetic test result may still have an increased risk for cancer based on their family history.