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PubMed This is a summary of 29 peer-reviewed journal articles Updated
Medical Genetics · Hereditary Breast and Ovarian Cancer

What Genes Besides BRCA Cause Breast & Ovarian Cancer?

At a Glance

While BRCA genes are the most well-known, mutations in other genes like PALB2, ATM, CHEK2, CDH1, and PTEN also increase the risk for hereditary breast and ovarian cancer. Multi-gene panel testing is now the standard way to identify these broader cancer risks.

In this answer

3 sections

01

High vs. Moderate Penetrance Genes

02

Why Multi-Gene Panels Are the Standard of Care

03

The Catch: Variants of Uncertain Significance (VUS)

For many years, the BRCA1 and BRCA2 genes were the primary focus when evaluating a person’s genetic risk for hereditary breast and ovarian cancer. However, we now know that changes (mutations) in several other genes can also significantly increase your risk for these and other cancers [1][2]. Because of this, modern genetic testing has moved away from looking only at BRCA1 and BRCA2. Today, multi-gene panels—tests that look at dozens of cancer-risk genes simultaneously—are the standard of care [3][4].

Discovering a genetic mutation can be overwhelming, especially when modern panels test for risks beyond just breast or ovarian cancer. This is why it is highly recommended to work closely with a genetic counselor who can help you prepare for these possibilities before you even take the test.

High vs. Moderate Penetrance Genes

Genes linked to cancer risk are often described by their penetrance, which simply means how likely it is that a person with a mutation in that gene will actually develop cancer during their lifetime [5].

High-Penetrance Genes

Mutations in these genes carry a very high lifetime risk for cancer. For context, these mutations can increase your breast cancer risk to more than four times that of the general population [6][7].

  • PALB2: Similar to BRCA mutations, changes in PALB2 carry a high risk for breast cancer, as well as an increased risk for ovarian and pancreatic cancers [8].
  • CDH1: This gene is strongly associated with a specific type of breast cancer called lobular breast cancer, carrying a lifetime breast cancer risk of around 37% [9][10]. It is also linked to hereditary diffuse gastric cancer. Because the stomach cancer risk is so severe, discussions around this gene often involve preventive stomach removal [11].
  • PTEN: Mutations here cause PTEN Hamartoma Tumor Syndrome (including Cowden syndrome), which significantly increases the risk for breast, thyroid, and uterine cancers [12][13]. A hamartoma is a type of non-cancerous growth.
  • TP53: Associated with Li-Fraumeni syndrome, mutations in this gene dramatically increase the risk for breast cancer (often at a very young age), as well as sarcomas (cancers of the bone or muscle), brain tumors, and other cancers [14]. Finding out you have a massive risk for unexpected cancers like brain tumors can be frightening, which is why a genetic counselor’s guidance is vital. People with this mutation must also be cautious with radiation therapy due to an impaired ability to repair DNA [15].

Moderate-Penetrance Genes

These genes increase your cancer risk, but not as severely as high-penetrance genes. They generally double or triple the average risk [5].

  • ATM and CHEK2: Both are linked to an increased risk of breast cancer (often estrogen-receptor positive) [14].
  • RAD51C, RAD51D, and BRIP1: These genes are primarily known for increasing the risk of ovarian cancer [1][16]. For instance, a mutation in BRIP1 is often considered a reason to discuss preventive removal of the ovaries and fallopian tubes between ages 45 and 50 [17]. While preventing cancer is the goal, it is important to acknowledge that this surgery forces the body into early menopause, significantly impacting a patient’s quality of life. Newer evidence shows RAD51C and RAD51D can also elevate breast cancer risk, depending heavily on your family history [18].

Why Multi-Gene Panels Are the Standard of Care

If you had genetic testing more than a decade ago (prior to 2014), you were likely only tested for BRCA1 and BRCA2. You should speak with a genetic counselor to see if you qualify for updated testing. Today, a single blood or saliva test can read a panel of many genes at once [19]. Multi-gene panels are the new standard for several reasons:

  • Finding More Answers: Testing multiple genes at once identifies significantly more people with hereditary cancer risks than BRCA-only testing [20][21]. This means families get more accurate explanations for their cancer history.
  • Tailored Screening: Knowing exactly which gene is altered changes how your medical team manages your health [22]. For example, if you have an ATM mutation, your doctor might recommend starting breast MRIs earlier [23][24], whereas a BRIP1 mutation shifts the focus primarily toward ovarian screening and prevention [17].
  • Cost and Efficiency: It is much more efficient and cost-effective to test for all relevant genes at once rather than testing them one by one [25].

The Catch: Variants of Uncertain Significance (VUS)

The main drawback of casting a wider net with multi-gene panels is a higher chance of finding a Variant of Uncertain Significance (VUS) [26][27]. A VUS means the laboratory found a change in your DNA, but there isn’t enough medical evidence yet to know if it increases your cancer risk or is just a harmless biological quirk.

It is crucial to know that a VUS is not a diagnosis. Standard medical guidelines recommend that a VUS should not be used to make decisions about preventive surgeries (like a mastectomy) [27][28]. In most cases, a VUS is eventually reclassified as harmless as researchers learn more [29].

Who tracks a VUS? It is generally the patient’s responsibility to check in with their genetic counselor or doctor every year or two to see if the laboratory has reclassified the variant. Discussing this communication plan with your care team upfront can relieve significant anxiety.

Common questions in this guide

What is a multi-gene panel for cancer risk?
A multi-gene panel is a single blood or saliva test that checks dozens of genes simultaneously for cancer-causing mutations, rather than just testing for BRCA1 and BRCA2. It provides a more comprehensive look at your hereditary cancer risk.
What are the high-penetrance genes for breast cancer besides BRCA?
High-penetrance genes like PALB2, CDH1, PTEN, and TP53 significantly increase your lifetime risk for breast cancer. Mutations in these genes may also elevate the risk for other unexpected cancers, such as ovarian, pancreatic, or stomach cancer.
What is a Variant of Uncertain Significance (VUS)?
A VUS means the genetic test found a change in your DNA, but there is not enough evidence to know if it increases your cancer risk or is just a harmless biological quirk. Most VUS results are eventually reclassified as harmless.
Should I have preventive surgery if I have a VUS?
Because a VUS is not a diagnosis and the risk is unclear, standard medical guidelines state it should not be used to make decisions about preventive surgeries like a mastectomy. You should track the VUS with your care team to see if it gets reclassified.
How do ATM and CHEK2 gene mutations affect my cancer risk?
Moderate-penetrance genes like ATM and CHEK2 generally double or triple your average cancer risk. While they may prompt your doctor to change your screening schedule, such as starting breast MRIs earlier, they are not as severe as high-penetrance genes.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Given my personal and family history of cancer, which specific multi-gene panel is most appropriate for me?
  2. 2.If my test returns a Variant of Uncertain Significance (VUS), what is the clinic's process for tracking it, and is it my responsibility to call you yearly to check for updates?
  3. 3.If I test positive for a moderate-penetrance gene like ATM or CHEK2, how exactly will that change the timeline and frequency of my current screening schedule?
  4. 4.Since multi-gene panels test for risks beyond breast and ovarian cancer, can you refer me to a genetic counselor to discuss how I might handle unexpected findings before I take the test?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

Related questions

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This page is for informational purposes only and does not replace professional medical advice. Always consult a genetic counselor or oncologist regarding genetic testing and personalized cancer risk management.

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