What Is BRCA2? About the BRCA2 Mutation and More

Learn how BRCA2 mutations impact cancer risk, how BRCA2-associated breast cancer is treated, and more

Breast cancer is the most common cancer among women in the United States after skin cancer. Age is the strongest risk factor for developing breast cancer, followed by family history. Most breast cancer cases are sporadic, or arising spontaneously, but in five to 10 percent of cases, the disease is caused by inherited gene mutations. This includes mutations in the well-known breast cancer susceptibility gene BRCA2.

Below we explore how the function of BRCA2 and how hereditary BRCA2 mutations can increase the risk of breast cancer.

What is the BRCA2 gene?

BRCA2 (BReast CAncer gene 2) is a gene that, when mutated, can increase a person’s lifetime risk of breast and other cancers, including ovarian, prostate, and pancreatic. Most breast cancers that arise from a BRCA2 gene mutation are estrogen receptor (ER)–positive/HER2-negative. BCRF investigator Dr. Alan Ashworth was a key part of the team that discovered the BRCA2 gene in 1995. In 1996, BCRF investigator Dr. Kenneth Offit and his team identified the most common BRCA2 mutation associated with breast and ovarian cancer among people with Ashkenazi Jewish ancestry.

How does the BRCA2 gene function?

The BRCA2 gene codes for breast cancer type 2 susceptibility protein, also called BRCA2. When it functions normally, BRCA2 is part of a group of proteins that repair DNA when both strands of its double helix are broken or when the strands are mismatched. Cells continually grow and divide and maintaining the integrity of each cell’s DNA is essential for normal cell function. This includes repairing any small errors that may occur during this process. If the DNA cannot be repaired, the BRCA2 protein can also trigger cellular responses to DNA damage that block cell division and induce cell death so that the damaged DNA is not passed on. In this way, BRCA2 is a tumor suppressor gene.

A mutation in the BRCA2 protein disrupts its normal DNA repair function. Once damaged, DNA is not repaired correctly, and a person’s risk of developing breast cancer increases.

What is the BRCA2 gene mutation?

Genes are sequences of DNA nucleotides that are the basic functional unit of heredity. The BRCA2 gene is a DNA sequence within a larger package of DNA called a chromosome. The BRCA2 gene provides the blueprint for cells to make the BRCA2 protein. Everyone has two copies of the BRCA2 gene—one from each parent—within our 23 pairs of chromosomes. Mutations, or changes in the DNA sequence, can be inherited from either parent and passed on to both sons and daughters equally. A mutation that is inherited is called a germline mutation.

Researchers have identified thousands of different mutations in BRCA2. Some of these BRCA2 gene mutations are harmful (pathogenic), some have no observed impact on health (benign), and some have uncertain significance. Though rare, people who inherit two mutated copies of the BRCA2 gene have a condition called Fanconi anemia, which causes low levels of functional BRCA2 protein along with impaired response to DNA damage, resulting in the accumulation of mutated DNA. People with Fanconi anemia are more susceptible to developing certain types of leukemia, other kinds of tumors, and reduced red blood cell production that causes anemia. While there is no cure for Fanconi anemia, treatments are available.

Inherited breast cancer risk is most commonly associated with BRCA1 and BRCA2 genes, though there are several established breast cancer susceptibility genes. Certain pathogenic variants of BRCA2 or of other breast cancer susceptibility genes can increase the risk of breast cancer as part of hereditary breast-ovarian cancer syndromes (HBOC). HBOC accounts for 90 percent of all hereditary breast cancers.

Since BRCA2 mutations can be passed to both sexes equally, families with HBOC have higher than normal rates of not only breast and ovarian cancers, but cholangiocarcinoma, gastric cancer, and melanoma as well. Because the term HBOC is misleading in that it implies that it affects women more than men, it is more recently also known as King syndrome, named for BCRF investigator Dr. Mary-Claire King, who discovered BRCA1.

How does a BRCA2 mutation impact breast cancer risk?

In the general population, about 12 percent of women in the U.S. will develop breast cancer in their lifetime. Women with a pathogenic BRCA2 mutation, in contrast, have a 45 to 69 percent lifetime risk of developing breast cancer. Pathogenic BRCA2 mutations also commonly give rise to ductal carcinoma in situ (DCIS), a non-invasive pre-cancer that’s also called stage 0. Of all breast cancer diagnoses arising from pathogenic BRCA2 mutations, about 75 percent are ER-positive, and 14 to 35 percent are triple-negative (TNBC), a more aggressive and difficult to-treat-subtype because it lacks many treatment targets.

Black women are more likely to be diagnosed with breast cancer at a younger age and with TNBC compared to white women. They are also more likely to have mutations in BRCA2 or PALB2, another breast cancer susceptibility gene, compared to their white counterparts. Women who are breast cancer survivors and have an inherited BRCA2 mutation have a three-fold increased risk of developing breast cancer in the opposite breast compared to the general population.

In men, the majority of BRCA2-associated breast cancers are also ER-positive but at a higher frequency than in women—about 90 percent. About 1.8 to 7.1 percent of men with an inherited pathogenic BRCA2 mutation will develop breast cancer by age 70 compared to 0.1 percent of the general population.

BRCA2 mutations across races/ethnicities

High-risk BRCA1—a related breast cancer susceptibility gene—or BRCA2 gene mutations are observed in about 0.2 to 0.3 percent of the general population, but among specific populations, the prevalence is higher. In fact, hereditary BRCA1 and BRCA2 mutations differ among geographic and ethnic populations and occur more in some groups. These harmful mutations arose in the ancestors of these populations that remained relatively isolated and were passed on through generations. These specific pathogenic BRCA1 and BRCA2 variants are called “founder” mutations and are frequently observed in certain groups.

For example, among people with Ashkenazi Jewish ancestry, there is a high prevalence of one BRCA2 founder mutation in about 2 percent of the population. Latin American, Norwegian, Dutch, West African, African American, Sephardi Jewish, Bahamian, and Icelandic populations also have unique BRCA2 founder mutations that lead to increased breast cancer risk. In the Icelandic population, which is relatively insulated, a single BRCA2 mutation accounts for nearly all the hereditary breast and ovarian cancer in the country.

BRCA1 vs. BRCA2

BRCA1 and BRCA2 are related genes that make distinct proteins that work together to repair DNA. Inheriting a harmful mutation in either BRCA1 or BRCA2 increases the risk of breast cancer, but the type of breast cancer they promote is different. While BRCA1-associated breast cancers are typically TNBC, BRCA2-associated breast cancers are more likely to be ER-positive.

Additionally, in women, the lifetime risk of ovarian cancer is higher for BRCA1—about 40 to 45 percent—compared to 10 to 20 percent for BRCA2. Men with a BRCA1 mutation have a 1 percent lifetime risk of breast cancer compared to a 6 percent lifetime risk for men with a BRCA2 mutation.

What to know about genetic testing for BRCA2

Genetic testing for hereditary BRCA2 and other breast cancer susceptibility gene mutations may be recommended based on your personal and family history of cancer, ancestry, and whether you have a family member with a genetic mutation. Because these mutations are inherited, they are present in the DNA of every cell in the body, including in saliva and blood. To conduct genetic testing, you’ll provide a saliva or blood sample for analysis.

Genetic counseling before testing is recommended to understand if you or your family members will likely to benefit from it. If you have a family history of breast cancer, a genetic counselor may recommend using a multigene panel test that looks for mutations in several breast cancer susceptibility genes. For those with Ashkenazi or Eastern European Jewish ancestry, a genetic counselor may recommend testing for the BRCA2 founder mutation commonly seen in that population. If a pathogenic BRCA2 mutation is found, parents, children, and siblings have a 50 percent chance of having the same mutation and may consider genetic testing.

If a pathogenic BRCA2 mutation is found in a person who does not have cancer, genetic counselors and clinicians can advise on the next steps to take to prevent breast cancer or find and treat it as early as possible. Because the risk of breast and ovarian cancer is significant, many BRCA2 mutation carriers choose to have risk-reducing surgery, removing both breasts (bilateral mastectomy) or both ovaries (bilateral prophylactic oophorectomy). Bilateral mastectomy reduces the risk of breast cancer by 95 percent in pathogenic BRCA2 mutation carriers.

If genetic testing does not reveal a BRCA2 mutation that was previously found in another family member, this indicates that the mutation was not inherited. Then, your risk for developing breast cancer is no higher than in the general population.

If a pathogenic BRCA2 mutation is found in a person who currently has breast cancer, knowing this information can help guide treatment decisions. If a BRCA2 mutation is not found, it is likely that the cancer was not caused by a hereditary BRCA2 mutation and testing family members is not likely to be helpful.

Researchers have identified BRCA2 variants of uncertain significance, meaning that researchers don’t yet know whether that particular mutation causes cancer. In this case, further testing may be available.

BCRF’s BRCA2 Research

BCRF investigators are working tirelessly to improve care for BRCA1 and BRCA2 mutation carriers and expand treatments for TNBC. BCRF investigators are improving genetic testing for families carrying breast cancer susceptibility gene mutations and populations at higher risk of having BRCA1 and BRCA2 founder mutations. Researchers are optimizing screening for BRCA1 and BRCA2 mutation carriers and working to introduce preventative options beyond risk-reducing surgery, including vaccines.

They are also working to better understand the risk conferred by the thousands of known BRCA1 and BRCA2 gene mutations and to turn this improved risk assessment into actionable care decisions. In 2025, BCRF investigator Dr. Fergus Couch and colleagues published significant findings from a study that clarified the risk of numerous BRCA2 variants of uncertain significance. Dr. Couch and his team classified 261 pathogenic variants that were previously considered to be variants of uncertain significance; ClinVar’s Expert Panel Review had previously established 14 pathogenic BRCA2 variants to date.

The majority (about 75 percent) of breast cancers arising from pathogenic BRCA2 mutations are ER-positive, but about 14 to 35 percent are TNBC. Little is known about the biology of BRCA2-driven breast cancers that are ER-positive, although it is thought to be associated with intrinsically less-favorable biology and a higher risk of recurrence.

BCRF researchers are working to better understand the biology of ER-positive, BRCA-associated breast cancer and refine treatments for TNBC. The discovery that TNBCs can differ from patient to patient and respond differently to therapies has been leveraged to develop new drugs and combinations to target an individual’s disease better.

• BCRF investigators are conducting clinical trials testing PARP inhibitors alone and in combination with other therapies for treating breast and ovarian cancer. PARP inhibitors target the “backup” DNA repair pathway used by cells when BRCA1- and BRCA2-mediated DNA repair is not functional because of a gene mutation. In BRCA-mutated breast cancer cells, regardless of ER status, PARP inhibitors inhibit “backup” DNA repair so they can no longer survive.

• BCRF researchers are profiling the biology of ER-positive, BRCA-driven breast cancers to explore how they differ from those without BRCA-associated mutations in order to refine treatment.

• Antibody-drug conjugates (ADCs) can deliver chemotherapy directly to cancer cells while sparing healthy cells. This technology has opened up new options for treating TNBC and some HER2-low breast cancers that were previously classified as TNBC. Trastuzumab deruxtecan (Enhertu®) received FDA approval in 2022 to treat HER2-positive advanced breast cancer with low levels of HER2, and in 2025, it was approved to treat advanced breast cancers with ultralow levels of HER2. The ADC sacituzumab govitecan (Trodelvy®) was FDA approved for metastatic TNBC in 2020 based on studies from BCRF investigators and others. Studies are ongoing to optimize ADC treatment for breast cancer.

• Researchers are also leveraging the immune system to eradicate cancer more effectively, particularly since immunotherapy has had some success in the clinic for treating TNBC. For example, ongoing studies are assessing checkpoint inhibitors, a form of immune therapy. They work by targeting and blocking certain proteins that act as “brakes” on the immune system, allowing it to recognize and attack cancer cells more effectively.

BCRF investigators are leading the way to improve how BRCA2 mutation carriers are treated. By investigating BRCA2 pathogenic mutations and TNBC from so many angles, our researchers stand to make significant strides in care for those who are at high risk of developing breast cancer.