Basser Research Center for BRCA

Genetic Risk Evaluation

Here you will find information on cancer risk evaluation, hereditary links between cancers, BRCA cancer risks and inheritance, and the genetic counseling and testing process. If you are a BRCA carrier and are looking for more information on cancer risks and managing risks, visit Cancer Risks. If you are concerned about the cost of genetic testing, visit our Insurance FAQ.

For a referral to a genetics professional in your area, visit the National Society of Genetic Counselors here.

If you live in the greater Philadelphia area,
contact us for an evaluation today.

Introduction to Cancer Risk Evaluation

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

Cancer Risk Evaluation involves reviewing one's personal and family history of cancer, and where appropriate, genetic testing to further define cancer risk.

Cancer Risk Evaluation Programs typically offer genetic counseling and testing for a variety of hereditary cancer conditions, including hereditary breast and ovarian cancer syndrome caused by mutations in the BRCA1 and BRCA2 genes.

Genes are the instruction manuals contained in all of our cells. Genes are made up of DNA which acts 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.

Cancer development is a multistep, complex process. Cells receive many instructions about when to grow and divide, and when to stop growing. If certain genes, like BRCA1 and BRCA2, have errors or mutations they stop working properly, 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.

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.

Most people develop cancer because of a series of gene mutations that occur for multiple reasons (e.g. environmental factors, lifestyle, random cell division errors) over many years. All of us develop mutations in our genes as we age. Some of these gene mutations will be repaired and some of these mutations will not. Most people with cancer are over the age of 50, since it takes time for these mutations to build up.

In families with hereditary forms of cancer risk, like BRCA1 and BRCA2, a mutation in either gene is present in all cells in the body. Inheriting a mutation in a gene that is associated with cancer risk may mean that your cancer risk is higher than someone who does not carry a mutation.

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.

Genes are inherited from your parents. All genes are present in pairs. A father contributes half of a pair of a child's genes in the sperm and the mother contributes the other half of each pair in the egg. The fertilized egg will then have two copies of each gene. Mutations in BRCA1 and BRCA2 are called dominant mutations. This is because having a mutation in only one copy of a BRCA1 or BRCA2 gene is enough to increase cancer risk.

You can think of a gene as a page in an instruction manual for the cells of the body. One gene in a pair may be mutated, but the other copy of this gene in the gene pair is normal and working properly. So, people with mutations in BRCA1 or BRCA2 are not born with cancer. However, these individuals are at increased risk of cancer because there is no back-up copy of this gene. There is no back-up page in the instruction manual for the body to refer to should something go wrong.

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 gene such as BRCA1 or BRCA2. Only about 5-10% of breast cancers, and 10-15% of ovarian cancers are strongly related to mutations in single high cancer risk genes. BRCA1 and BRCA2 are responsible for many hereditary breast and ovarian cancers but there are other gene mutations that increase risk for these cancers.

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.

Inherited mutations in the genes BRCA1 and BRCA2 are rare. Only about 1 in 500 to 1 in 800 individuals have a mutation.

However, these gene mutations are more common in certain ethnic groups. For example, those of Eastern or Central European Jewish descent (Ashkenazi Jewish) have a 1 in 40 chance of having a BRCA1 or BRCA2 mutation.

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.

BRCA Cancer Risks and Inheritance of BRCA

A complete personal and family history, including at least three generations of relatives should be examined to determine if a mutation is present in a high risk cancer gene. Be sure to collect information from both your mother and father's sides of your family before meeting with a genetics specialist.

The following features are associated with hereditary cancer:

  • Multiple generations of people affected with the same or related cancers (for example, breast, ovarian, pancreatic, prostate and melanoma cancers are more common in families with mutations in BRCA1 and BRCA2)
  • At least some people with cancer diagnosed at early ages for that cancer
  • Some people in the family may have more than one type of cancer, like a woman with both breast and ovarian cancer
  • Presence of rare cancers in the family, such as male breast cancer.

Any of the above warrant genetic counseling but not all families with a single one of these characteristics will need to undergo genetic testing.

A positive BRCA1 or BRCA2 result means that a person has an inherited mutation in either gene and is at increased risk for certain cancers. The cancer risks associated with BRCA1 and BRCA2 in men and women carrying mutations are presented as ranges (see Table 1).

Table 1: Cancer Risk Ranges for BRCA1 and BRCA2 carriers

Lifetime BRCA1 and BRCA2 Cancer Risks for Women
   

Women with BRCA1 Mutation

Women with BRCA2 mutation

Average woman in US without mutation

Type of Cancer

Breast

60-80%

50-70%

13%

Ovarian

30-45%

10-20%

1-2%

Pancreatic

2-3%

3-5%

1%

Melanoma

-

3-5%

1-2%

 

Lifetime BRCA1 and BRCA2 Cancer Risks for Men

   

Men with BRCA1 Mutation

Men with

BRCA2

mutation

Average man in US without mutation

Type of Cancer

Breast

1-5%

5-10%

0.1%

Prostate

*

15-25%*

16%

Pancreatic

2-3%

3-5%

1%

Melanoma

-

3-5%

1-2%

* Although there is no convincing evidence of overall increased risk of prostate cancer, men with BRCA1 mutations may develop prostate cancer at a younger age than men in the general population. BRCA2 mutations are associated with an increased risk of prostate cancer, which also can be of earlier onset.

For more information on cancer risks in BRCA carriers, see Cancer Risks.

Learning about the presence or absence of a BRCA gene mutation can help guide medical care. A person with a gene mutation may benefit from more frequent check-ups and screening tests starting at earlier ages than someone who does not have a gene mutation.

People with mutations in BRCA1 or BRCA2 may develop one, none or several cancers. Unfortunately, being diagnosed with one type of cancer does not mean that other cancer risks no longer apply. For example, women with BRCA mutations, who have developed one breast cancer, are at increased risk of developing a second breast cancer (up to 50-60 percent chance of a second breast cancer over the course of one's lifetime), as well as ovarian and other cancers.

A parent who has a mutation in BRCA1 or BRCA2 has a 50% chance of passing the mutated gene on to each of their children, and a 50% chance of passing along the normal copy of the gene to each of their children.

Men as well as women can inherit and pass on a mutation in BRCA1 or BRCA2 to either a son or daughter.

Each time someone has a child, the same 50-50 chance is present to pass along either the normal or mutated gene.

Gene mutations in BRCA1 and BRCA2 do not skip a generation. A child who does not inherit a BRCA mutation from a parent cannot then pass a BRCA mutation to the next generation.

A parent with a BRCA mutation may pass the mutation along to one, some or none of their children.


Genetic Testing FAQ

Genetic testing is typically a blood test, or a collection of cheek cells with 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. Mutations in BRCA genes lead to an increased risk of breast and ovarian cancer.

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.

A relative with cancer may either be unavailable or unwilling to be tested. In this situation, testing can still be performed on someone not affected with cancer. Through the genetic counseling process, you will understand what testing strategy will be most informative for your family.

Deciding whether or not to have genetic testing is a personal decision. A mutation in BRCA1 or BRCA2 can alter your medical management, increase the chance of detecting a cancer early when it is most treatable, and open up options for decreasing cancer risk.

Therefore, when to have genetic testing should also be considered. For example, testing young adults may not be beneficial, since medical decision-making may not be affected for several years (not until 25 for women and 35-40 for men). Genetic test results for BRCA1 and BRCA2 would only be medically relevant during these periods if an individual chooses to use reproductive technology to avoid passing the gene mutation on. Currently, children are not candidates for BRCA 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 choose whether or not to be tested.

Possible 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 facilitating 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, and following the latest research on possible interventions.
  • 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.
  • Some individuals with a known mutation in their family will learn they did not inherit a gene mutation, and are not at high risk in spite of their strong family history of cancer.
  • Some individuals will learn they did inherit a gene mutation and will then have more information to alter their cancer risk management.

Possible limitations of genetic testing include:

  • The state-of-the-art genetic testing may not find all BRCA gene mutations. Some mutations may not be detectable using the current state-of-the-art technology, though this possibility is remote. The genetic counseling process should inform people about what the significance of a negative result (not finding a mutation) will be.
  • BRCA1 and BRCA2 are not the only genes that increase the risk of certain cancers, so a negative result may not rule out hereditary cancer risk.
  • Testing is expensive and while insurance often covers the cost, it may not. Information about insurance coverage can be obtained before testing decisions are made.
  • The possibility that finding a genetic mutation could cause worry, anxiety or other emotional distress.
  • The possibility of finding a variant of unknown clinical significance in BRCA1 or BRCA2 for which cancer risk is not currently known.
  • There is a remote possibility of genetic discrimination for some people.

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.


BRCA Test Results FAQ

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. See below.

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

A positive result means that you have a deleterious mutation in either the BRCA1 or BRCA2 gene. The printed result will indicate which gene has a mutation. This result means that you have increased cancer risks and need to be managed differently. Please see Cancer Risks to learn more about what it means to be BRCA positive.

Until the source of cancer risk in a family is known, it is hard to know the significance of a negative result (meaning that no mutation is found) for those who are cancer free.

If there is a different gene, perhaps an undiscovered one not yet available for testing that underlies a family history of cancer, then a BRCA test result may not detect the most important indicator of risk in a cancer-free individual.

Over time, the laboratory will usually reclassify the variant result, meaning they will determine if the alteration in the gene increases cancer risk or not. Most variant results are later reclassified as polymorphisms- normal changes in the gene- that do not increase cancer risk.

Families with variants are usually managed based on the family history and NOT based on the variant result. A genetics specialist may be able to research your variant and speak with the laboratory to gain a little more information about the likelihood that your variant increases cancer risk or not.

Regardless of a genetic testing result, it is important to remember that anyone can develop cancer, whether or not a cancer risk gene mutation is present. The significance of your negative result depends entirely on your personal and family history and can be interpreted by genetics specialist.

Remember that most cancer in the general population is not a result of these inherited gene mutations. A person who does not inherit a familial cancer-risk gene mutation has a much lower risk, but they are still at average risk for cancer, so screening recommendations for the early detection of cancer for the general population still need to be followed.

Negative BRCA Results: When A Family Mutation is Known

When someone has been tested and a BRCA mutation has been found, then the source of cancer risk for the family is known. If other individuals in the family are tested and receive negative results, then these individuals are no longer at increased risk for developing BRCA-related cancers. This is a "true negative" result.

If there is no other family history or significant risk factor, these individuals may begin to follow cancer screening recommendations for an "average" risk person, and not a high-risk person. In addition, an individual with a negative result cannot pass the family mutation on to his or her children.

Negative BRCA Results: When a Family Mutation is Unknown

When no one in the family has been found to have a detectable BRCA mutation, negative test results need to be interpreted with caution. In this setting, a negative result may not really be negative.

We know that mutations in the BRCA1 and BRCA2 genes do not explain all hereditary patterns of breast and ovarian cancer. A family may have a mutation in a different gene, perhaps not yet discovered or whose clinical implications are not yet fully known. Unless there is a known mutation in the family, a negative result from BRCA testing does not exclude genetic risk for an individual.

A personalized cancer risk management program can be developed for individuals known to be at increased cancer risk due to a mutation in BRCA1 or BRCA2. A cancer risk management plan is typically tailored to a person's unique circumstances and preferences. Generally, cancer that is detected in earlier stages is more easily treated, and outcomes are often more favorable. You and your doctors will ultimately decide what plan makes the most sense for you.

Cancer risk management generally includes the following categories:

  • Intensive screening to optimize the chances of early detection, should cancer develop.
  • Consideration of prophylactic or risk reducing surgical removal of ovaries and possibly breast tissue.
  • Chemoprevention, which is taking a medicine thought to lower the chances of developing cancer.

More details on cancer risks and cancer risk management for BRCA carriers can be found here.