What to Know About PALB2 Mutations and Breast Cancer Risk

Learn how the PALB2 gene functions and how hereditary PALB2 mutations impact breast cancer risk

Most breast cancers are sporadic, meaning they occur without any known cause or risk factors. Several factors, however, can significantly increase a woman’s risk of developing the disease, including older age, a family history of breast cancer, and inherited genetic mutations.

Most people are familiar with BRCA1 and BRCA2, the most commonly mutated genes associated with increased breast cancer risk, but other gene mutations confer an increased risk of developing the disease, including one called PALB2. Increased breast cancer risk in families with pathogenic PALB2 mutations was first shown over a decade ago in a seminal study that was co-authored by several BCRF investigators.

Here, we discuss how PALB2 gene mutations increase breast cancer risk and how BCRF is advancing research on this and other breast cancer–associated gene mutations.

What’s the PALB2 gene and how does it function?

PALB2 (partner and localizer of BRCA2) is a gene that encodes a protein that’s also called PALB2. When it functions normally, the PALB2 protein works with the BRCA2 protein to repair DNA when both strands of the double helix are broken or when the strands are mismatched. PALB2 is a linker between BRCA2 and BRCA1—an interaction that’s critical for DNA repair.

Maintaining DNA is essential for cells to function normally. PALB2, BRCA2, and other proteins ensure damage to the DNA is repaired or that damaged DNA that cannot be repaired is destroyed. A mutation in the PALB2 gene disrupts the normal function of PALB2 protein and the DNA repair process. Damaged DNA that goes unrepaired can ultimately lead to cancer.

What is an inherited PALB2 gene mutation?

The PALB2 gene, like all genes, is a sequence of DNA nucleotides inside a larger package of DNA called a chromosome. DNA is the basic functional unit of heredity. The PALB2 gene provides the blueprint for cells to make the PALB2 protein. Everyone inherits a copy of the PALB2 gene in their chromosomes from each parent. Mutations, or changes in the DNA sequence, can be inherited from either parent and passed on to both sons and daughters equally. PALB2 mutations are inherited in an autosomal dominant pattern, meaning that a person only needs to inherit one copy of the gene from either parent that has a pathogenic (disease-causing) mutation to be at increased risk of developing cancer.

Though rare, people who inherit two mutated copies of the PALB2 gene have a condition called Fanconi anemia, which causes low levels of functional PALB2 protein that results in impaired response to DNA damage and the accumulation of mutated DNA. People with Fanconi anemia are at increased risk for childhood cancer and are more susceptible to developing certain types of leukemia and reduced red blood cell production that causes anemia. While there is no cure for Fanconi anemia, treatments are available.

How does a PALB2 mutation impact breast cancer risk?

A PALB2 gene mutation can significantly increase a woman’s risk of developing breast and ovarian cancers. The lifetime risk of developing breast cancer for women with a PALB2 mutation is estimated to be around 35 to 40 percent, compared to around 12 percent in the general population, 55 to 72 percent in BRCA1 carriers, and 45 to 69 percent in BRCA2 carriers. The estimated lifetime risk of ovarian cancer also increases about 10 to 15 percent. While breast cancer is more common in women, a PALB2 mutation can increase the risk of prostate cancer in men. PALB2 mutations are also associated with increased risk of pancreatic cancer and melanoma.

Breast cancers arising from pathogenic PALB2 mutations are associated with all subtypes of breast cancer, but most—about 75 percent—are estrogen receptor (ER)–positive and about 20 percent are triple-negative (TNBC), an aggressive form that is difficult to treat because it lacks many known treatment targets. This is a similar subtype distribution as› BRCA2 (see PALB2 vs. BRCA below).

Black women are more likely to have mutations in PALB2 or BRCA2 compared to white women and are more likely to be diagnosed with breast cancer at a younger age and with TNBC. The U.S.-based Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, supported in part by BCRF, sought to improve the accuracy of breast cancer risk assessment for all populations of women without a history of the disease. The study analyzed breast cancer susceptibility genes beyond BRCA1 and BRCA2. CARRIERS conducted the first large study to identify breast cancer predisposition genes in an African ancestry population. The study found that mutations in PALB2 as well as BRCA1 and BRCA2 were linked with high risks of developing breast cancer and estimates that Black women with pathogenic PALB2 mutations have a 58 percent lifetime risk of developing breast cancer, compared to 35 to 40 percent lifetime risk across all groups.

How common is a PALB2 mutation?

PALB2 is the most common breast cancer susceptibility genes after BRCA1 and BRCA2. Even so, germline (inherited) and somatic (not inherited) variants of PALB2 are relatively rare. PALB2 mutations in breast cancer patients range from 0.1 to 2.7 percent, depending on the population, and are found in one to four percent of families with breast cancer who are not BRCA1 or BRCA2 carriers.

PALB2 vs. BRCA

PALB2 works closely with BRCA2 to repair DNA damage, and the effects of PALB2 vs. BRCA2 in breast cancer are similar. The increase in breast cancer risk associated with pathogenic PALB2 mutations is comparable to risk conferred by pathogenic BRCA2 mutations. PALB2-associated breast cancers also have a similar subtype distribution as BRCA2, with the majority ER-positive, HER2-negative.

Cells that are PALB2 deficient are sensitive to PARP inhibitors like BRCA-deficient cells. PARP inhibitors target the “backup” DNA repair pathway used by cells when the DNA repair pathway mediated by BRCA1, BRCA2, and PALB2 is not functional. PARP inhibitors block this alternative DNA repair so that affected cells are unable to survive.

What to know about PALB2 genetic testing

Genetic testing is important for determining breast cancer risk and may be recommended based on your personal or family history of breast cancer or whether you have a family member with a genetic mutation. Because these mutations are inherited, they are found in the DNA of every cell in the body, including blood and saliva cells that are easily collected for testing.

Since discovery of the connection of PALB2 to hereditary breast cancer risk, PALB2 is now standard in genetic testing for breast cancer. Genetic tests to evaluate for hereditary breast cancer risk often consist of a panel of genes, including BRCA1, BRCA2, PALB2, and others.

Because genetic testing of PALB2 has not been available for as long as genetic testing of BRCA1 and BRCA2, patients who were tested before 2013 may not have had the PALB2 gene analyzed. If a pathogenic PALB2 mutation is found, parents, children, and siblings have a 50 percent chance of having the same mutation and may also consider genetic testing.

If a person tests positive for a pathogenic PALB2 gene mutation, next steps may include a personalized screening and early detection plan, risk-reduction options such as surgery, and biomarker and further genetic testing to determine which treatments may work best for that individual.

How BCRF is advancing PALB2 research

BCRF investigators are working to improve care for families with PALB2 gene mutations and advance treatments for breast cancers arising from PALB2.

Ten to 15 percent of women with a personal or family history of breast cancer have mutations in genes other than BRCA1 or BRCA2. Genetic tests for PALB2 and other, lesser-studied breast cancer susceptibility genes are being improved to provide more information and nuanced genetic counseling on exact levels of risk. Researchers have identified hundreds of mutations in PALB2 and other genes associated with breast cancer that are being used to further refine and improve risk assessment for developing breast cancer. In turn, this deeper understanding of risk can lead to more informed decisions about preventive and screening care.

About 75 percent of breast cancers arising from pathogenic PALB2 mutations are ER-positive, but about 20 percent are TNBC, which aligns with the subtype distribution of BRCA2-driven breast cancers. Little is known about the biology of these breast cancers that are ER-positive. BCRF researchers are working to better understand the biology of ER-positive breast cancers arising from BRCA2 or PALB2 and refine treatments for TNBC.

• 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 PALB2-, BRCA1-, or BRCA2-mediated DNA repair is not functional because of a gene mutation. In BRCA- or PALB2-mutated breast cancer cells, regardless of ER status, PARP inhibitors inhibit “backup” DNA repair so they can no longer survive.
• 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 and -ultralow breast cancers that were previously classified as TNBC. Trastuzumab deruxtecan (Enhertu®) received FDA approval in 2022 to treat metastatic HER2-positive 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 there has been some success using immunotherapy to treat 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.

Since discovering its link to hereditary breast cancer, BCRF investigators have made significant advancements in understanding the function of PALB2 and risks associated with pathogenic PALB2 gene mutations. Our researchers continue to uncover the biology of PALB2-driven breast cancer and refine genetic testing and risk assessment—improving care for those at risk of hereditary breast cancer.