Reviewed by 2 medical advisers
Cristina Nixon, MS, LCGC Main Line Health Genetics and Risk Assessment Program, Narberth, PA Peggy Cottrell, MS, LCGC Sharsheret, Teaneck, NJ
About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.
Genes are short segments of DNA (deoxyribonucleic acid) found in chromosomes. DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.
Think of your genes as an instruction manual for cell growth and function. Changes or mistakes in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. This is like having an instruction manual in which all the copies have the same typographical error.
There are two types of DNA changes: those that are inherited and those that happen over time. Inherited DNA changes are passed down from parent to child. Inherited DNA changes are called germ-line alterations or mutations.
DNA changes that happen over the course of a lifetime, as a result of the natural aging process or exposure to chemicals in the environment, are called somatic alterations.
Some DNA changes are harmless, but others can cause disease or other health issues. DNA changes that negatively affect health are called mutations.
BRCA1 and BRCA2 genetic mutations
Most inherited cases of breast cancer are associated with mutations in two genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).
Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast, ovarian, and other cells growing normally. But when these genes contain mutations that are passed from generation to generation, the genes don't function normally and breast, ovarian, and other cancer risk increases. BRCA1 and BRCA2 mutations may account for up to 10% of all breast cancers, or 1 out of every 10 cases.
Having a BRCA1 or BRCA2 mutation doesn't mean you will be diagnosed with breast cancer. Researchers are learning that other mutations in pieces of chromosomes — called SNPs (single nucleotide polymorphisms) — may be linked to higher breast cancer risk in women with a BRCA1 mutation as well as women who didn't inherit a breast cancer gene mutation.
Women who are diagnosed with breast cancer and have a BRCA1 or BRCA2 mutation often have a family history of breast cancer, ovarian cancer, and other cancers. Still, most people who develop breast cancer did not inherit a genetic mutation linked to breast cancer and have no family history of the disease.
You are substantially more likely to have a genetic mutation linked to breast cancer if:
- You have blood relatives (grandmothers, mother, sisters, aunts) on either your mother's or father's side of the family who had breast cancer diagnosed before age 50.
- There is both breast and ovarian cancer on the same side of the family or in a single individual.
- You have a relative(s) with triple-negative breast cancer.
- There are other cancers in your family in addition to breast, such as prostate, melanoma, pancreatic, stomach, uterine, thyroid, colon, and/or sarcoma.
- Women in your family have had cancer in both breasts.
- You are of Ashkenazi Jewish (Eastern European) heritage.
- You are Black and have been diagnosed with breast cancer at age 35 or younger.
- A man in your family has had breast cancer.
- There is a known abnormal breast cancer gene in your family.
If one family member has a genetic mutation linked to breast cancer, it does not mean that all family members will have it.
The average woman in the United States has about a 1 in 8, or about 12%, risk of developing breast cancer in her lifetime. Women who have a BRCA1 mutation or BRCA2 mutation (or both) can have up to a 72% risk of being diagnosed with breast cancer during their lifetimes. Breast cancers associated with a BRCA1 or BRCA2 mutation tend to develop in younger women and occur more often in both breasts than cancers in women without these genetic mutations.
Women with a BRCA1 or BRCA2 mutation also have an increased risk of developing ovarian, colon, and pancreatic cancers, as well as melanoma. Men who have a BRCA2 mutation have a higher risk of breast cancer than men who don't — about 8% by the time they're 80 years old. This is about 80 times greater than average.
Men with a BRCA1 mutation have a slightly higher risk of prostate cancer. Men with a BRCA2 mutation are 7 times more likely than men without the mutation to develop prostate cancer. Other cancer risks, such as cancer of the skin or digestive tract, also may be slightly higher in men with a BRCA1 or BRCA2 mutation.
Preliminary research suggests that a BRCA2 mutation in children and adolescents may be linked to a higher risk of non-Hodgkin lymphoma. Lymphoma is cancer of the lymph system.
Inherited mutations in other genes are also associated with breast cancer. These abnormal gene changes are much less common than BRCA1 and BRCA2 mutations, which themselves are fairly uncommon. Also, most of them don't seem to increase breast cancer risk as much as abnormal BRCA1 and BRCA2 genes. Still, because these genetic mutations are rare, they haven't been studied as much as the BRCA genes.
Based on research to date, experts have estimated the levels of breast cancer risk that may be associated with each gene mutation. Levels of genetic risk are generally defined as:
- High risk: Lifetime breast cancer risk is estimated to be greater than 50%.
- Moderate to high risk: Lifetime breast cancer risk estimates range anywhere from 25% to over 50%.
- Moderate risk: Lifetime breast cancer risk is estimated at about 25% to 50%.
- Uncertain risk: There isn’t enough evidence from research studies to link the mutation with an increase in breast cancer risk, but it has been linked with ovarian cancer risk and possibly other cancers.
Below is a list of other genes besides BRCA1 and BRCA2 that sometimes have abnormal changes that run in families with a strong history of breast cancer and other cancers. Most have been linked to some increase in breast cancer risk; others haven’t yet, but that may change over time.
If you have one of these mutations, keep in mind that your own personal risk of breast cancer may be lower or higher than the estimated risks below, depending on the details of your family history. As research continues, the risk levels associated with each mutation are likely to change. Also, the estimated risk levels cited are for women, as most of this research has not focused on men. There is some evidence linking ATM, CHEK2, and PALB2 mutations with male breast cancer, along with BRCA1 and BRCA2, but more research is needed to understand those risks.
Always check with your care team for the latest information.
High risk gene mutations
- PALB2: The PALB2 (partner and localizer of BRCA2) gene provides instructions to make a protein that works with the BRCA2 protein to repair damaged DNA and stop tumor growth. Research suggests that women with a PALB2 mutation have a 14% risk of developing breast cancer by age 50, but that risk jumps to 35% by age 70. And for those with a family history, the risk of breast cancer by age 70 is 58%. In comparison, women with an abnormal BRCA1 gene have a 50% to 70% risk of developing breast cancer by age 70. Women with an abnormal BRCA2 gene have a 40% to 60% risk of developing breast cancer by age 70.
- PTEN: The PTEN gene helps regulate cell growth. An abnormal PTEN gene causes Cowden syndrome, a rare disorder in which people have a higher risk of both benign (not cancer) and cancerous breast tumors, as well as growths in the digestive tract, thyroid, uterus, and ovaries. The lifetime breast cancer risk for women with a PTEN mutation is estimated at 25% to 50%, although some studies have reported a higher risk, at 77% to 85%. The average age at diagnosis is 38 to 50 years.
- TP53: The TP53 gene provides instructions to the body for making a protein that stops tumor growth. Inheriting an abnormal TP53 gene causes Li-Fraumeni syndrome, a disorder in which people develop soft tissue cancers at a young age. People with this rare syndrome have a higher-than-average-risk of breast cancer and several other cancers, including leukemia, brain tumors, and sarcomas (cancer of the bones or connective tissue). A study by the National Cancer Institute suggested women with Li-Fraumeni syndrome have a 54% risk of developing breast cancer by age 70. Also, women with this syndrome tend to develop breast cancer at earlier ages and may be more likely to have HER2-positive cancers. The risk of getting any type of cancer in women with a TP53 mutation is up to nearly 100%. In men, it is up to 73%. This gender difference is mostly due to the high breast cancer risk in women.
Moderate to high risk gene mutations
- ATM: The ATM gene helps repair damaged DNA. DNA carries genetic information in cells. Inheriting two abnormal copies of this gene causes ataxia-telangiectasia, a rare disease that affects brain development. Inheriting one abnormal ATM gene has been linked to an increased rate of breast cancer and pancreatic cancer in some families. That’s because the abnormal gene stops the cells from repairing damaged DNA. Research suggests that ATM mutation carriers have a 33% to 38% lifetime risk of developing breast cancer (by age 80). However, for those with a certain type of mutation affecting a specific location on the ATM gene, the lifetime risk is estimated to be 69%.
- CDH1: The CDH1 gene makes a protein that helps cells bind together to form tissue. An abnormal CDH1 gene increases the risk of a rare type of stomach cancer at an early age. The lifetime risk for this stomach cancer is up to 83%. Women with an abnormal CDH1 gene also have a 39% to 52% lifetime risk of invasive lobular breast cancer.
Moderate risk gene mutations
- CHEK2: The CHEK2 gene provides instructions for making a protein that stops tumor growth. An abnormal CHEK2 gene can at least double the lifetime risk of breast cancer. It can also increase colorectal and prostate cancer risk. For women with CHEK2 mutations and a family history of breast cancer, the lifetime risk of breast cancer is estimated to range from 28% to 37%. However, the risk may be higher depending on the number of family members affected by breast cancer.
- NBN: The NBN gene controls production of a protein called nibrin, which helps repair DNA damage in cells. An abnormal NBN gene causes Nijmegen breakage syndrome, a condition that results in slow growth in infancy and early childhood. People with Nijmegen breakage syndrome are shorter than average, have a higher risk of several types of cancer (including breast cancer), and have many other health problems. Research is limited, but studies suggest that people with certain NBN mutations may have a two- to three-times greater lifetime risk of developing breast cancer.
- NF1: An NF1 mutation causes a condition called neurofibromatosis type 1, which increases the risk of central nervous system cancers and a specific type of cancer that grows in the wall of the stomach or intestines, called gastrointestinal stromal tumors. The lifetime risk of cancer overall is nearly 60%. Some studies have suggested that women with an NF1 mutation are at higher risk of developing breast cancer, especially before age 50.
- STK11: The STK11 gene helps regulate cell growth. An abnormal STK11 gene causes Peutz-Jeghers syndrome, a rare disorder in which people tend to develop a type of polyp, called a hamartomatous polyp, mostly in the small intestine but also in the stomach and colon. In addition to gastrointestinal cancers, people with Peutz-Jeghers syndrome are also at higher risk of breast cancer, lung cancer, and ovarian tumors. People with Peutz-Jeghers syndrome may also develop freckling around the eyes, nose, and mouth, as well as inside the mouth. In women with Peutz-Jeghers syndrome, the lifetime risk of breast cancer (by age 70) is estimated to be about 45%. Before age 50, the risk is similar to that of the general population.
Genetic mutations with uncertain breast cancer risk
Other gene mutations are sometimes found in families with a strong history of cancer. Mutations in the genes listed below may or may not cause an increased risk of breast cancer. Further research is needed to tell what the increased breast cancer risk is, if any.
- BARD1: BARD1 (BRCA1 Associated Ring Domain 1) is a gene that works with BRCA1 to repair damaged DNA. Some studies have suggested that BARD1 mutations can increase breast cancer risk.
- BRIP1: The BRIP1 gene also works to repair DNA. Right now, a BRIP1 mutation is associated with a higher lifetime risk of ovarian cancer. There is not enough evidence to link it with increased breast cancer risk.
- MLH1, MSH2, MSH6, PMS2, EPCAM: All of these are called mismatch repair genes, and they work to repair any mistakes that occur when DNA copies itself. Inherited mutations in these genes lead to a condition known as Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC). People with Lynch syndrome are at higher risk of colorectal cancer and other cancers, including endometrial and ovarian cancer. Some research suggests that the MLH1 and MSH2 mutations may be linked to an increased risk of breast cancer.
- RAD51C and RAD51D: These genes are involved in repairing DNA damage. Both have been linked to a small increase in the lifetime risk of ovarian cancer. They have not been linked to elevated breast cancer risk.
Inheriting two abnormal copies of the BRCA2, BRIP1, NBN, PALB2, or RAD51C genes causes the disease Fanconi anemia, which suppresses bone marrow function and leads to very low levels of red blood cells, white blood cells, and platelets. People with Fanconi anemia also have a higher risk of several other types of cancer, including kidney cancer and brain cancer.
There are genetic tests available to determine if someone has inherited an abnormal BRCA1 or BRCA2 gene. A genetic counselor also may order testing for mutations in the ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 and/or MLH1, MSH2, MSH6, PMS2, EPCAM genes. They can be tested for individually or as part of a larger gene panel that includes BRCA1 and BRCA2. Decisions about what tests to perform are based on your personal or family history of breast cancer and other cancers.
Steps you can take
If you know you have an abnormal gene linked to breast cancer, there are lifestyle choices you can make to keep your risk as low it can be:
- maintaining a healthy weight
- exercising regularly
- limiting alcohol
- eating nutritious food
- never smoking (or quitting if you do smoke)
These are just a few of the steps you can take. Review the other breast cancer risk factors for more options.
Along with these lifestyle choices, there are other risk-reduction options for women at high risk because of abnormal genetics.
Hormonal therapy medicines: Two SERMs (selective estrogen receptor modulators) and two aromatase inhibitors have been shown to reduce the risk of developing hormone-receptor-positive breast cancer in women at high risk.
- Tamoxifen has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in both postmenopausal and premenopausal women at high risk. Certain medicines may interfere with tamoxifen's protective effects. Visit the Tamoxifen page to learn more.
- Evista (chemical name: raloxifene) has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women. Visit the Evista page to learn more.
- Aromasin (chemical name: exemestane), an aromatase inhibitor, has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women at high risk. Aromasin isn’t approved by the FDA for this use, but doctors may consider it a good alternative to tamoxifen or Evista. In 2013, the American Society of Clinical Oncology (ASCO) released new guidelines on using hormonal therapy medicines to reduce breast cancer risk in high-risk women. These guidelines recommend that doctors talk to high-risk postmenopausal women about using Aromasin to reduce risk. ASCO is a national organization of oncologists and other cancer care providers. ASCO guidelines give doctors recommendations for treatments that are supported by much credible research and experience. Visit the Aromasin page for more information.
- Arimidex (chemical name: anastrozole), also an aromatase inhibitor, has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women at high risk. Like Aromasin, Arimidex isn’t approved by the FDA for this use, but doctors may consider it a good alternative to tamoxifen, Evista, or Aromasin. Visit the Arimidex page for more information.
Hormonal therapy medicines do not reduce the risk of hormone-receptor-negative breast cancer.
More frequent screening: If you're at high risk because of an abnormal breast cancer gene, you and your doctor will develop a screening plan tailored to your unique situation. You may start being screened when you're younger than 40. In addition to the recommended screening guidelines for women at average risk, a screening plan for a woman at high risk may include:
- a monthly breast self-exam
- a yearly breast exam by your doctor
- a digital mammogram every year starting at age 30 or younger
- an MRI scan every year starting at age 30 or younger
Women with an abnormal breast cancer gene need to be screened twice a year because they have a much higher risk of cancer developing in the time between yearly screenings. For example, the Memorial Sloan-Kettering Cancer Center in New York, NY recommends that women with an abnormal BRCA1 or BRCA2 gene have both a digital mammogram and an MRI scan each year, about 6 months apart (for example, a mammogram in December and an MRI in June).
A breast ultrasound is another powerful tool that can help detect breast cancer in women with an abnormal breast cancer gene. This test does not take the place of digital mammography and MRI scanning.
Talk to your doctor, radiologist, and genetic counselor about developing a specialized program for early detection that addresses your breast cancer risk, meets your individual needs, and gives you peace of mind.
Protective surgery: Removing the healthy breasts and ovaries — called prophylactic surgery ("prophylactic" means "protective") — are very aggressive, irreversible risk-reduction options that some women with an abnormal BRCA1 or BRCA2 gene choose.
Prophylactic breast surgery may be able to reduce a woman's risk of developing breast cancer by as much as 97%. The surgery removes nearly all of the breast tissue, so there are very few breast cells left behind that could develop into a cancer.
Women with an abnormal BRCA1 or BRCA2 gene may reduce their risk of breast cancer by about 50% by having prophylactic ovary and fallopian tube removal (salpingo-oophorectomy) before menopause. Removing the ovaries lowers the risk of breast cancer because the ovaries are the main source of estrogen in a premenopausal woman’s body. Removing the ovaries doesn’t reduce the risk of breast cancer in postmenopausal women because fat and muscle tissue are the main producers of estrogen in these women. Prophylactic removal of both ovaries and fallopian tubes reduces the risk of ovarian cancer in women at any age, before or after menopause.
Research also has shown that women with an abnormal BRCA1 or BRCA2 gene who have prophylactic ovary removal have better survival if they eventually are diagnosed with breast or ovarian cancer.
The benefit of prophylactic surgeries is usually counted one year at a time. That’s why the younger you are at the time of surgery, the larger the potential benefit, and the older you are, the lower the benefit. Also, as you get older you’re more likely to develop other medical conditions that affect how long you live, such as diabetes and heart disease.
Of course, each woman's situation is unique. Talk to your doctor about your personal level of risk and how best to manage it.
It's important to remember that no procedure — not even removing both healthy breasts and ovaries at a young age — totally eliminates the risk of cancer. There is still a small risk that cancer can develop in the areas where the breasts used to be. Close follow-up is necessary, even after prophylactic surgery.
Prophylactic surgery decisions require a great deal of thought, patience, and discussion with your doctors, genetic counselor, and family over time — together with a tremendous amount of courage. Take the time you need to consider these options and make decisions that feel comfortable to you.
For more information, visit the Breastcancer.org Prophylactic Mastectomy and Prophylactic Ovary Removal pages.
Reviewed by 2 medical advisers:
Cristina Nixon, MS, LCGC Main Line Health Genetics and Risk Assessment Program, Narberth, PA Peggy Cottrell, MS, LCGC Sharsheret, Teaneck, NJ
This information is provided by Breastcancer.org.