Beyond BRCA: Understanding Breast Cancer Gene Mutations

While BRCA1 and BRCA2 are well known genes, there are others that can increase the risk of breast cancer. Here’s what the latest research reveals.

Key Takeaways

• About 5–10% of breast cancer cases are linked to inherited gene mutations.
• BRCA1 and BRCA2 are the most well-known breast cancer genes, but 11 other mutations also increase risk.
• Mutations in genes like PALB2, ATM, TP53, CDH1, PTEN, STK11, and CHEK2 can raise the risk of breast cancer to varying degrees.
• BCRF-funded research continues to uncover how these mutations affect risk, prevention, and treatment

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 gene mutations are relatively rare in the general population, affected individuals face a much higher risk of the disease.

You’ve no doubt heard of BRCA1 and BRCA2, which get most of the attention in conversations around breast cancer and genetics because they confer the highest risk. However, they’re not the only genes with mutations linked to an increased risk of breast cancer. Researchers have discovered at least 11 breast cancer susceptibility genes in addition to BRCA1 and BRCA2, according to Facing Our Risk of Cancer Empowered (FORCE)—with many others still being studied. Ongoing research on mutations in these genes may open doors for developing more tailored risk assessment, early detection, prevention strategies, and treatment options.

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

What are breast cancer gene mutations?

Breast cancer 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 key genes that regulate cell growth and repair and increase the likelihood of uncontrolled cell growth, a hallmark of 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, even if none of your relatives has been diagnosed, you may still carry a breast cancer gene mutation that increases your risk.

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 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 breast cancer susceptibility genes 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

The most well-known breast cancer genes were discovered by BCRF investigators in the mid-1990s: BRCA1 by Mary-Claire King, PhD and BRCA2 by Alan Ashworth, PhD. The BRCA genes play a key role in helping the body repair damaged DNA. Thousands of variations can occur in BRCA1 and BRCA2 gene sequences. Many don’t have a clear impact on cancer risk and are called variants of uncertain significance, but some variants can interfere with the body’s ability to repair damaged DNA, leading to abnormal cell growth and potentially breast and other cancers.

According to the 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 12.5 percent. Those who carry these mutated genes may be at even higher risk if multiple members of their family have had the disease. Women with BRCA1 or BRCA2 mutations have a greater risk of developing breast cancer in both breasts, either at the same time or sequentially, and BRCA1- and BRCA2-associated breast cancers tend to occur in 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. 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 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 Island, Greenland, the prevalence ranges from one in 10 to one in 100. Other groups likely to have a harmful BRCA mutation include people of Dutch, French Canadian, Icelandic, and Norwegian descent.

Other breast cancer gene mutations beyond BRCA1 and BRCA2

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.

Read on to learn about several breast cancer gene mutations beyond BRCA1 and BRCA2.

PALB2 mutation

The PALB2 gene (short for Partner and Localizer of BRCA2) also plays a role in repairing DNA damage in cells: PALB2 produces a protein that interacts with BRCA1 and BRCA2 to form a functional DNA repair complex. Variants of this gene can prevent the protein from functioning properly, potentially allowing cells with damaged DNA to multiply and form tumors.

In 2014, several BRCF investigators and their colleagues found that PALB2 mutations may be among the most important breast cancer gene 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 as much as nine-fold for women and eight-fold for men.

ATM mutation

The ATM gene plays a key role in controlling cell division and repairing DNA, making it a particular focus for 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 12.5 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 mutation

The TP53 gene encodes 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 the 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 mutation

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, or 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 to 50 percent lifetime risk of developing lobular breast cancer.

PTEN mutation

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 mutation

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. They may also present an elevated risk of many types of cancer, including breast.

Women with STK11 mutations have a 32 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 mutation

Sometimes called a “cancer protection gene,” CHEK2 encodes 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 lifetime, according to FORCE. Variants of the CHEK2 gene are more common in cases of estrogen receptor-positive breast cancer.

Some data show that some breast cancer patients with this mutation may face a higher risk of a second breast cancer diagnosis within a 10-year period. We need more research to understand how CHEK2 mutations may affect the risk of a second breast cancer diagnosis.

Evolving research on breast cancer gene mutations

While inherited breast cancer gene mutations are rare, understanding their impact is crucial for improving screening, prevention, and treatment strategies. BCRF-funded investigators have led the way in identifying key mutations, such as those in BRCA1, BRCA2, and PALB2. Their work has deepened our understanding of how inherited mutations affect breast cancer risk and treatment outcomes.

This research not only enhances our knowledge but also helps shape new screening guidelines and therapies, ensuring that scientific discoveries directly impact patients’ lives. With ongoing advancements in genetic testing, we are making significant progress in identifying individuals at high risk, developing preventive interventions, and optimizing treatment strategies for those diagnosed with breast cancer.

BCRF plays a vital role in supporting this groundbreaking research. By funding the world’s leading scientists, BCRF ensures that each discovery brings us closer to better screening, prevention, and treatment options for those at risk.

Make an impact today and support BCRF’s mission to fund innovative research on breast cancer gene mutations

Frequently asked questions about breast cancer gene mutations

References and research sources

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