Beyond BRCA: What to Know About Other Gene Mutations Linked to Breast Cancer

You’ve no doubt heard of BRCA1 and BRCA2, but there are other known genetic mutations that can raise the risk of breast cancer. Here’s what the latest research reveals

DNA can play a major role in a person’s odds of developing breast cancer. An estimated five to 10 percent of all breast cancer cases may be directly linked to changes (mutations) in genes passed on from a parent, according to the American Cancer Society (ACS). While breast cancer–associated gene mutations are relatively rare in the general population, affected individuals face a much higher risk of the disease.

BRCA1 and BRCA2 get most of the attention in conversations around breast cancer and genetics because they confer the highest risk. However, they’re not the only mutations linked to an increased risk of breast cancer. Researchers have discovered at least 11 breast cancer–associated gene mutations in addition to BRCA1 and BRCA2, according to Facing Our Risk of Cancer Empowered (FORCE)—with many others still being studied. Ongoing research on these mutations may open doors for more tailored risk assessment, early detection, prevention strategies, and treatment options.

Here’s what you need to know about breast cancer–associated gene mutations, including those in BRCA1 and BRCA2, as well as their lesser-known counterparts.

What are breast cancer–associated gene mutations?

Breast cancer–associated gene mutations are harmful changes in certain DNA segments that can increase an individual’s likelihood of developing the disease. While some mutations are harmless, others affect essential cellular processes, increasing the likelihood of uncontrolled cell growth that can turn into cancer.

Like other genetic code, these mutations can be inherited. Generally speaking, you receive two copies of each gene—one from each parent. So, if one parent has a mutation in one of their genes, there’s a 50 percent chance that you’ll inherit it. This genetic link explains why having a family history of hereditary breast cancer puts you at higher risk of developing the disease. However, genetic mutations can still increase your risk of breast cancer, even if none of your relatives have ever been diagnosed.

In a 2021 study, BCRF investigators analyzed inherited data from nearly 65,000 women, about half of whom were breast cancer patients, and found that between 30 and 50 percent of breast cancer–associated gene mutations occur in women who wouldn’t typically be considered high risk, including those without a family history of the disease.

So far, researchers have shown that mutations in at least 13 genes are linked to an increased risk of breast cancer. Some of the known gene mutations include:

• ATM
• BARD1
• BRCA1
• BRCA2
• CDH1
• CHEK2
• NF1
• PALB2
• PTEN
• RAD51C
• RAD51D
• STK11
• TP53

This list isn’t exhaustive. According to the online resource My Cancer Genome run by Vanderbilt University Medical Center, researchers continue to investigate whether mutations in dozens of other genes, such as MUTYH, BRIP1, and MRE11A, may also increase a person’s risk of breast cancer. As genetic research evolves, scientists can develop new biomarker-directed therapies, improve screening guidelines, and provide more precise prevention recommendations for patients with known mutations.

About BRCA1 and BRCA2

Discovered in the mid-1990s, BRCA1 and BRCA2 are the most well-known breast cancer–associated genes—and the first to have been identified. The BRCA genes play a key role in helping the body repair damaged DNA. Thousands of mutations can occur in BRCA1 and BRCA2 genes. While most are variants that don’t increase risk or are variants of uncertain significance that don’t have a clear impact on cancer risk yet (research is changing that), some variants or mutations can interfere with the body’s ability to repair damaged DNA, leading to abnormal cell growth that can result in breast and other cancers.

According to ACS, up to about 70 percent of women with a BRCA1 or BRCA2 mutation will develop breast cancer in their lifetime—a figure that’s significantly higher than the average American woman’s lifetime risk of 13 percent. Those who carry these mutated genes may be at even higher risk if multiple members of their family have had the disease. Breast cancers arising from BRCA1 and BRCA2 mutations have a higher likelihood of appearing in both breasts and tend to affect women at younger ages.

BRCA1 or BRCA2 mutations don’t just affect women—they increase the risk of breast and other cancers (prostate, pancreatic) in men, as well. For men in the general population, the chance of developing breast cancer by age 70 is about 0.1 percent, according to the National Cancer Institute. But for those with a BRCA mutation, the risk is much higher. An estimated 0.2 percent to 1.2 percent of men with a BRCA1 mutation and 1.8 percent to 7.1 percent of men with a BRCA2 mutation will be diagnosed with breast cancer. Given the rarity of breast cancer in men, it’s unclear whether those with a BRCA1 or BRCA2 mutation face a higher likelihood of cancer in both breasts.

While these harmful breast cancer–associated gene mutations can significantly affect an individual’s risk, they’re relatively rare in the general population. The BRCA1 and BRCA2 variants known to increase the risk of ovarian and breast cancer affect about one in every 400 to 500 people, according to research from the early 2000s.

However, these mutations are significantly more prevalent in certain ethnic groups. Among individuals of Ashkenazi Jewish descent, roughly one in 40 carries a BRCA mutation, while in Inuit populations from Ammassalik, Greenland, the prevalence ranges from one in 10 to one in 100. Other groups likely to have a BRCA mutation include people of Dutch, French Canadian, Icelandic, and Norwegian descent.

Mutations in genes other than BRCA1/2

Though they are less well known, mutations in other genes can also increase the risk of developing the disease. Scientists have identified several of these mutations, each with varying degrees of risk. While rare, these mutations can still play a significant role in hereditary breast cancer and may influence screening and prevention strategies.

Here are some gene mutations—other than those in BRCA1/2—to know.

PALB2 mutations

The PALB2 gene (short for Partner and Localizer of BRCA2) also helps repair DNA damage in cells. It works closely with the BRCA2 gene, producing a protein that supports the DNA repair process. Variants of this gene can prevent the protein from functioning properly, potentially allowing cells with damaged DNA to multiply and form tumors.

In 2014, BRCF investigators found that PALB2 mutations may be among the most important breast cancer–associated mutations influencing a person’s risk. Though PALB2 mutations account for just one to two percent of inherited breast cancer cases, they increase the lifetime risk of breast cancer nine-fold for women and eight-fold for men.

ATM mutations

The ATM gene plays a key role in controlling cell division and repairing DNA, making it a particular focus in cancer research. Inheriting a mutated copy can increase a person’s risk of breast cancer, with some variants posing a greater threat than others.

According to FORCE, people with an ATM mutation face up to twice the lifetime risk of breast cancer compared to the general population. One specific variant, c.7271T>G, has been linked to a 60 percent lifetime risk of developing breast cancer by age 80—far higher than the estimated 13 percent risk for the average woman.

Breast cancer isn’t the only disease associated with ATM mutations. Those who inherit two mutated copies of this gene can develop ataxia telangiectasia, a rare childhood neurological disorder that’s also linked with acute lymphocytic leukemia or lymphoma.

TP53 mutations

The TP53 gene helps create a protein that regulates cell division and suppresses tumor formation. Some inherited TP53 mutations cause Li-Fraumeni Syndrome, which is associated with a significantly higher risk of breast cancer, leukemia, brain tumors, and sarcomas (cancer of the bones or connective tissue), according to ACS. A 2016 study published in the journal Cancer showed that women who carry an inherited TP53 mutation have an 85 percent risk of developing breast cancer by age 60.

CDH1 mutations

The CDH1 gene provides instructions for making E-cadherin, a protein that helps cells stick together to form tissues. Inherited CHD1 mutations can lead to hereditary diffuse gastric cancer, a cancer disorder that’s also associated with an increased risk of lobular breast cancer (a type of cancer that originates in the milk-producing glands, known as lobules). Variants in the CDH1 gene may directly account for a small fraction of breast cancer cases, as well.

Women with CDH1 mutations face a 40 percent to 50 percent lifetime risk of developing lobular breast cancer.

PTEN mutations

The PTEN gene helps manage cell reproduction. PTEN mutations passed down from a parent can cause a rare disorder known as Cowden Syndrome (CS) or PTEN hamartoma tumor syndrome (PHTS), which can increase the risk of breast cancer and many other types of cancer.

Individuals with a PTEN mutation are 85 percent more likely to develop any type of cancer at some point in their lives. The risk of breast cancer is especially high, affecting between 41 and 60 percent of women with PTEN mutations, according to FORCE.

STK11 mutations

The STK11 gene provides the code to make an enzyme that suppresses tumors. More than 340 STK11 mutations have been found in people with Peutz-Jeghers Syndrome (a rare condition in which polyps form in the intestines), which comes with an elevated risk of many types of cancer, including breast.

Women with STK11 mutations have a 32 percent to 54 percent lifetime risk of developing breast cancer, according to FORCE. Research from 2020 also indicates that STK11 mutations have been linked with early breast cancer recurrence after standard treatment.

CHEK2 mutations

Sometimes called a “cancer protection gene,” CHEK2 provides the code for a protein that suppresses the growth of tumors. Women with inherited CHEK2 mutations have a 20 to 40 percent chance of developing breast cancer during their lives, according to FORCE. Variants of the CHEK2 gene are more common in cases of estrogen receptor–positive breast cancer.

Some data show that breast cancer patients with mutations in CHEK2 who do not undergo a double mastectomy face a higher risk of a second breast cancer diagnosis within a 10-year period. More research is needed to understand how CHEK2 mutations may affect the risk of a second breast cancer diagnosis.

Evolving research on gene mutations linked to breast cancer

While inherited breast cancer–associated gene mutations are rare, understanding their impact can lead to better screening, prevention, and treatment strategies for patients. BCRF investigators have been at the forefront of research into inherited mutations; they’ve discovered mutations including those in BRCA1, BRCA2, and PALB2, and they’ve worked to better understand the impacts of inherited mutations on breast cancer risk and treatment.

With more research and improvements in genetic testing, we’ll make strides in determining who is most at risk of breast cancer, devising interventions to prevent the disease, and optimizing treatment after a diagnosis.