GENETIC TESTING

a general overview

This information is for general information only and may not apply to you. Also it gets out of date as medicine progresses. Please check with your provider prior to any action or concern. You must remember it is in general positive results are dealing with probabilities of getting the disease and if positive may adversely affect you mentally causing anxiety and depression

Genes contain information about how you look and how your body works; they are passed from parents to children (inherited).

Genetic testing looks for abnormalities (also called ” harmful( pathogenic) variants, alterations, or mutations) in certain genes. The result of genetic testing can help you understand your risk for developing certain diseases, such as breast, ovarian, prostate, or pancreatic cancer. Testing for pathogenic variants in several different genes is available. 

Pathogenic variants have different implications, depending on whether they are carried in the “germline” (inherited from a parent or happening during early embryonic development) or “acquired” (arising at any time in a person’s life e.g exposure to radiation)

In hereditary cancer syndromes, the pathogenic variant is present in the germline, meaning it is present in an egg or sperm cell and passed from parent to child at the time of conception. If a person inherits a germline variant, it is usually present in every cell in their body. This means that the person may be at risk for several types of tumors over their lifetime.

They may benefit from increased monitoring to detect cancer at an earlier and more treatable stage and/or interventions such as prophylactic (preventive) surgery to lower the risk of developing cancer.

If you have inherited a germline pathogenic variant, it also means that you could pass it on to your children. This differs from cancers in which genetic variants found in the tumor cannot be passed on to children. However, some families may have a high risk of breast or ovarian cancer caused by a gene variant that has not yet been identified, and increased monitoring or other interventions may be appropriate in family members without cancer. In every situation a consultation with a hereditary cancer or cancer genetics expert is essential.

Between 5 and 10 percent of breast cancers and up to 20 percent of ovarian cancers are caused by germline variants. Approximately 10 to 15 percent of pancreatic and metastatic prostate cancers are due to genetic causes. The genes most often involved are known as BRCA1 and BRCA2.

Genetic testing for hereditary breast, ovarian, pancreatic, and prostate cancers includes analysis of the BRCA1 and BRCA2 genes for pathogenic variants.

There is also “next-generation” multigene or panel testing, which includes analysis of a number of genes in which variants are associated with hereditary cancer. For example, panels may assess only those genes in which variants are associated with very high risks of certain cancers. Larger panels may also include more moderate-risk genes or newer genes, for which less information is known about cancer risks and the management recommendations may be less clear. Genetic testing is done on a sample of saliva or blood.

WHO SHOULD CONSIDER GENETIC TESTING?

Your health care provider can help you understand your personal and family history and whether you might be a candidate for genetic counseling and testing. Ultimately, the decision is up to you.

Commonly used guidelines — In general, experts typically recommend genetic counseling and consideration of BRCA1/2 testing if you have (or have had):

●A personal history of breast cancer that falls into any of the following categories:

•Diagnosed at age 50 or younger, or 60 or younger for “triple-negative” breast cancer (a type of breast cancer that lacks proteins on the surface of its cells called estrogen and progesterone hormone receptors and human epidermal growth factor 2 [HER2] receptors [ie, ER, PR, and HER2 negative]).

•Cancer in both breasts (either at the same time or at separate times), with the first one diagnosed at age 50 or younger.

•Male breast cancer.

•Diagnosed at any age, in addition to having one or more close relatives with breast cancer at age 50 or younger or ovarian, male breast, metastatic prostate, or pancreatic cancer at any age.

●A personal history of ovarian, pancreatic, or metastatic prostate cancer.

●A personal and/or family history (on the same side of the family) of three or more of certain types of cancer (including, but not limited to, breast, colon, and pancreatic cancer).

●No personal history, but first- or second-degree relatives with breast cancer diagnosed at age 50 or younger, ovarian cancer, male breast cancer, pancreatic cancer, or metastatic prostate cancer.

●Ashkenazi Jewish ancestry (from Central or Eastern Europe), regardless of personal or family history, but especially if there is a personal history of breast, ovarian, pancreatic, or metastatic prostate cancer.

●One or more biological relatives who have tested positive for a pathogenic variant in BRCA1 or BRCA2, or other genes associated with hereditary cancer.

There are other situations in which genetic counseling and/or testing may also be recommended. An individualized risk assessment can help you determine whether genetic testing might be useful for you. Your health care provider can assess your personal risk; there are different tools and mathematical models they can use for this.

If you have not had cancer and are concerned about hereditary risk (for example, if you have had multiple relatives with breast or ovarian cancer), the usual recommendation is to offer testing first to someone in the family who has had cancer, if possible.

Usually this means testing a woman with ovarian cancer or breast cancer who was diagnosed at the youngest age within the family. If that person is found not to have a harmful variant, it may not be helpful to test family members without cancer.

Some companies sell at-home testing kits (these are also called “direct-to-consumer” tests). Usually the kits involve paying a fee and mailing in a sample of your saliva to a lab for testing. While some of these companies test only for genes that give information about your ancestry, others have expanded to test for pathogenic variants that can increase your risk of certain cancers, such as BRCA1 and BRCA2. However, these tests may not be comprehensive as they may only look at a small subset of the possible pathogenic variants in these genes, and/or they may not look at other genes that are also associated with hereditary cancers. In addition, if you choose to take one of these at-home tests and get a positive result, it’s important that you submit another sample to a clinical lab for confirmation.

If you are interested in this type of testing, you should discuss this with your health care provider or a genetic counselor first. They can help make sure you understand your results as well as the limitations of these tests.

GENETIC TESTING PROCESS

Pretest counseling — Before you have genetic testing, it is important to speak with a genetics or health care provider to better understand your level of risk for cancer. This involves a discussion of your personal and family history in order to better understand your risk for getting cancer in the future. The provider may also use mathematical models or calculators to help estimate your risk and discuss the following:

●Your options for genetic testing

●The risks, benefits, and limitations of testing

●The potential outcomes of the recommended test(s)

●The potential impact of your test results on family members

If you are interested in talking with a genetic counselor or genetics service provider, your health care provider can help you find one in your area.

Costs and insurance coverage — Genetic testing is offered by many different labs. The cost can vary widely depending on the extent of testing that is performed.

Many people worry about how the results of genetic testing will affect the chance of getting health or life insurance in the future. In the United States, a federal law known as the Genetic Information Nondiscrimination Act (GINA) prohibits health insurers and most employers with 15 or more employees from using your genetic information to discriminate against you. This law is intended to encourage Americans to take advantage of genetic testing if needed. In general, the law means that:

●Most employers cannot deny you a job or fire you because of the results of genetic testing.

●Health insurers cannot use genetic testing results to deny you coverage or set your insurance rates.

●Employers and insurers cannot require you to have genetic testing.

It’s important to be aware that the law does not have protections for disability, life insurance, or long-term care insurance. In addition, GINA does not apply to individuals in the military. State laws may provide additional coverage.

INTERPRETING THE RESULTS

It is not always easy to interpret the results of genetic tests. The results may be:

●Positive for a BRCA1 or BRCA2 or other harmful variant – This means that a variant was identified that is known to be associated with increased risks for cancer. It does not mean that you have cancer or will definitely get it.

●Negative, meaning that you do not have a variant in the genes that were tested – This result does not rule out the possibility that you may still have a hereditary risk for cancer. It is possible that your genetic testing did not include all known genes associated with cancer, nor all variants known to be present in the gene(s) tested. In addition, there are unknown genetic variants that have not yet been discovered.

●A “true” negative result – This means that a pathogenic variant that is present in one or more of your family members (for example, your mother, sibling, or aunt) was ruled out in you. This result usually means that your cancer risks are about the same as other people in the general population. However, your health care provider or genetic counselor will assess your other risk factors for cancer.

●Positive for a variant of “unknown significance” (VUS) – This means that you have a genetic change or variant, but it is not clear whether it increases your risk of cancer; it is possible to have a variant that does not affect cancer risk. Over time, most VUS results are reclassified as positive or negative. More often than not, most VUS results are reclassified as negative. It is important to keep in contact with your health care provider to ensure that you will receive updated information if this happens.

It’s important to keep in mind that a negative result does not mean that you will not develop cancer, and a positive result does not mean that you will definitely develop cancer.

The following is information specific to pathogenic variants in the BRCA1/2 genes. For information about other genes associated with hereditary breast and ovarian cancer, talk with your genetic counselor or health care provider.

For people who test positive for a BRCA1/2 pathogenic variant, the lifetime risk of developing certain types of cancer is estimated as follows:

●Female breast cancer – The lifetime risk (to age 70) of breast cancer is between 55 and 70 percent for BRCA1 and 45 to 70 percent for BRCA2. This means that in a group of 100 women with BRCA1, between 55 and 70 of the women will develop breast cancer in their lifetime. Some women may develop more than one breast cancer over the course of their lifetimes, sometimes on the opposite side compared to where their first breast cancer developed (in such cases, called “contralateral breast cancer”).

●Ovarian cancer – The lifetime risk of ovarian cancer is about 40 percent for BRCA1 and 15 percent for BRCA2.

●Male breast cancer – The lifetime risk of male breast cancer is about 1 percent for BRCA1 and 8 percent for BRCA2.

●Pancreatic cancer – The lifetime risk of pancreatic cancer is about 2 to 4 percent for BRCA1 and 5 percent for BRCA2.

●Prostate cancer – The lifetime risk of pancreatic cancer is about 15 to 20 percent for BRCA1 and 30 to 40 percent for BRCA2.

POST-TEST COUNSELING

After genetic testing is done, it is important to talk to your health care provider or genetics provider to make sure you understand what the results mean for you and your family. During this discussion you can find out how your test results affect your cancer risk and what options are available to you to detect cancer early or reduce your risk. Your health care provider or genetic counselor will answer your questions as well as provide resources for more information and support.

If you test positive for a pathogenic variant in a gene such as BRCA1 or BRCA2, it is important that you talk with your family about the results. Family members may want to talk to their own provider and/or obtain genetic counseling to discuss the option of genetic testing.

MANAGING THE RISK OF CANCER

If you test positive for a BRCA1/2 pathogenic variant, there are several ways to screen for cancer and to reduce your risk of developing cancer.

For women, you may

●Have more frequent screening for breast and ovarian cancer

●Have surgery to reduce your risk of breast and/or ovarian cancer

●Take a medicine to reduce your risk of breast or ovarian cancer

For men, you may have more frequent prostate cancer screening.

The best strategy might include a combination of these methods. It is important to understand that the aim of screening is to detect a cancer at its earliest stage, when it is most likely to be curable. The aim of prevention (or risk-reducing strategies) is to reduce the risk of ever developing cancer.

If you test negative for a BRCA1/2 pathogenic variant but have a family history of breast or ovarian cancer, talk to your health care provider about ways to manage your risk of developing cancer.

Screening options

Breast cancer screening — Increased screening is recommended for both women and men with a BRCA1/2 pathogenic variant.

Women who have a BRCA1/2 pathogenic variant are usually advised to have:

●A breast exam, performed by a health care provider, every 6 to 12 months beginning at age 25

●A mammogram once per year, beginning at age 30 (or possibly earlier, depending on family history)

●A breast magnetic resonance imaging (MRI) once per year, beginning at age 25 (or possibly earlier, depending on family history)

●”Breast awareness,” beginning at age 18, which involves paying attention to changes in the breasts and may include regular breast self-exams

Men who have a BRCA1/2 pathogenic variant are usually advised to have:

●Monthly breast self-examinations, beginning at age 35, in order to be aware of any changes in the breasts

●A breast exam, performed by a health care provider, every 12 months beginning at age 35

Men are not routinely advised to get mammograms for screening, although it may be considered in certain situations.

Ovarian cancer screening — In general, screening tests for ovarian cancer are not very accurate in detecting the disease. However, screening may be an option for some women who have a BRCA1/2 variant. This involves a combination of a blood test (called “CA 125”) and a pelvic ultrasound. Some experts recommend this combination of tests every six months, beginning at age 30 (or earlier, if the woman had a relative who was diagnosed with ovarian cancer before 30).

Prostate cancer screening — Men with a BRCA2 pathogenic variant should begin prostate cancer screening at age 40. Men with a BRCA1 pathogenic variant might also consider beginning screening at age 40; other factors, such as the age at diagnosis of any family members who had cancer, may influence the recommendation

Risk-reducing options

Surgery — An alternative to frequent cancer screening is surgery to reduce your risk of developing cancer. This is called preventive (or prophylactic) surgery, and it can significantly decrease your risk of cancer and may help decrease anxiety. Your health care provider can talk to you in detail about the potential risks and benefits of each type of preventive surgery.

The following may be options for reducing cancer risk in women with a BRCA1/2 pathogenic variant; there are no proven risk-reducing surgical options for men.

Mastectomy — Women who have both breasts removed (called “prophylactic bilateral mastectomy”) reduce their chance of developing breast cancer by at least 90 percent. There is a small chance of developing cancer in the residual breast tissue that remains after surgery.

Women who already have breast cancer may also choose to have one or both breasts removed to reduce their risk of developing a second breast cancer. More information about mastectomy, and options for breast reconstruction, is available separately.

Removal of the ovaries — Having the ovaries and fallopian tubes removed (termed a “prophylactic bilateral salpingo-oophorectomy,” or BSO) has been shown to reduce a woman’s risk of ovarian and fallopian tube cancer by 80 to 90 percent, and in premenopausal BRCA2 carriers, it may reduce the risk of breast cancer by 50 to 60 percent.

Women with a BRCA1/2 pathogenic variant are strongly recommended to have a BSO, typically between ages 35 and 40 years (for BRCA1) and 40 and 45 (BRCA2) and once they are done having children.

Medicines to reduce the risk of cancer — There is some evidence that certain medications can reduce the risk of cancer in women in particular situations:

●Medicines such as selective estrogen receptor modulators (eg, tamoxifen) or aromatase inhibitors have been shown to reduce the risk of breast cancer in women who are at increased risk not due to genetic reasons. Based on limited studies, it is possible that these medications are also effective in BRCA2 carriers, but it is unclear if they are in BRCA1 carriers. (

●Hormonal birth control (pill, skin patch, vaginal ring, shot, progestin intrauterine device [IUD], or implant) can decrease the risk of ovarian cancer. Data suggest that this is also true for women with a BRCA1/2 pathogenic variant.

However, it is possible that hormonal birth control may increase the risk of breast cancer, particularly in women who have a BRCA1 pathogenic variant and start birth control at a young age and before their first pregnancy. If you have a BRCA1/2 pathogenic variant, talk to your health care provider about the risks and benefits of hormonal birth control.