Germline Mutations in Ovarian Cancer: Understanding Genetic Risk and Testing

Every year, tens of thousands of women face an ovarian cancer diagnosis. And while there are multiple ovarian cancer risk factors, germline mutations (the inherited genetic changes passed down through families) play one of the most significant roles in determining who develops this disease and how they might respond to treatment.

Yet most people who carry a hereditary mutation linked to ovarian cancer have no idea. They haven’t been tested. They don’t know they’re at elevated risk. And they can’t take action on information they don’t have.

What Is a Germline Mutation?

A genetic mutation is a permanent change in your DNA sequence. Think of DNA as an instruction manual written with four letters: adenine (A), thymine (T), guanine (G), and cytosine (C). When these letters get scrambled, deleted, or duplicated, it creates a mutation.

But not all mutations spell trouble.

Germline mutations are genetic changes inherited from a parent. They’re present in every cell of your body from the moment of conception, and they can be passed on to your children. In the context of ovarian cancer, germline mutations matter because they disrupt crucial processes like DNA repair, which can create the right conditions for cancer to develop.

It’s worth knowing that there’s a second category of mutations called somatic mutations, which develop during your lifetime within specific cells, including tumor cells. 

Somatic mutations can’t be inherited, but they matter enormously for treatment decisions, particularly around targeted therapies. We’ll be covering somatic mutations in ovarian cancer in a separate article. For now, this piece focuses on germline mutations: what they are, which ones raise ovarian cancer risk, and why genetic testing for ovarian cancer may be one of the most important steps you can take.

Why Germline Mutations Matter for Ovarian Cancer

Ovarian cancer is notoriously difficult to detect early. There’s no reliable ovarian cancer screening test for the general population, and symptoms often don’t appear until the disease has already advanced.

That’s why understanding your genetic risk profile is so critical. It’s one of the few genuinely proactive steps that can change outcomes.

Up to 20% of ovarian cancer cases are linked to an inherited genetic mutation. That’s not a small number. But only 39% of patients have been referred to genetic counseling, and just 30% have completed genetic testing, despite major medical organizations recommending universal genetic testing for anyone diagnosed with epithelial ovarian cancer.

Knowing your genetic status doesn’t just inform your own care. It can protect the people you love, too.

Common Germline Mutations Linked to Ovarian Cancer

Let’s take a closer look at different types of germline mutations associated with ovarian cancer.

BRCA1 and BRCA2: The Most Significant Risk Factors

When most people think about genetic testing and cancer, they think about BRCA1 and BRCA2. And for good reason. These are the most well-known and most common germline mutations linked to ovarian cancer.

BRCA1 and BRCA2 genes are your cellular repair crew. When functioning normally, they fix dangerous DNA breaks that could lead to cancer. When they carry harmful mutations, that repair system fails.

The numbers are striking:

• BRCA1 mutations: 39 to 46% lifetime ovarian cancer risk (compared to about 1.3% in the general population)
• BRCA2 mutations: 10 to 27% lifetime ovarian cancer risk
• Recent 2024 data shows that approximately 1 in 400 women carry BRCA mutations, and also ~ 1 in 40 Ashkenazi Jewish women

Learn more about BRCA testing for ovarian cancer.

Lynch Syndrome: Beyond Colorectal Cancer

Lynch syndrome affects a group of DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. While it’s best known for raising colorectal cancer risk, it also significantly impacts ovarian cancer likelihood, accounting for another 10 to 15% of hereditary epithelial ovarian cancer cases.

Ovarian cancer risk by gene in Lynch syndrome:

• MSH2 mutations: 8–38% lifetime risk
• MLH1 mutations: 1–13% lifetime risk
• MSH6 mutations: 1 to 2% lifetime risk
• PMS2 mutations: risk still being studied

Women with Lynch syndrome often develop ovarian cancer at younger ages and may benefit from earlier discussions about preventive surgery, including hysterectomy and bilateral salpingo-oophorectomy.

RAD51C and RAD51D

RAD51C and RAD51D mutations carry a lifetime ovarian cancer risk of approximately 10–15% and 10–20% respectively, representing a relative risk of roughly 8 times that of the general population for both genes. They are increasingly included in comprehensive hereditary cancer panels, particularly in families with multiple ovarian cancer cases.

BRIP1

BRIP1 is linked to a cumulative lifetime ovarian cancer risk of approximately 5 to 15%, roughly 2.6 times the general population risk.

PALB2

PALB2 is closely connected to BRCA2’s function in DNA repair and carries an absolute lifetime ovarian cancer risk of approximately 3–5%. While NCCN acknowledges it as a meaningful contributor to hereditary ovarian cancer risk with strong supporting evidence, guidance on risk-reducing salpingo-oophorectomy (RRSO) for PALB2 carriers remains cautious. NCCN recommends considering rather than routinely performing RRSO, reflecting some inconsistency in the data across major organizations including ASCO, SSO, and ASTRO.

ATM

ATM mutations carry approximately 2–3% lifetime ovarian cancer risk. However, NCCN considers the data insufficient to recommend RRSO based on ATM status alone — decisions around risk-reducing surgery should be guided by individual family history rather than the mutation in isolation.

Taken together, pathogenic variants in BRCA1, BRCA2, BRIP1, RAD51D, RAD51C, PALB2, and mismatch repair genes account for approximately 20% of ovarian cancer cases overall.

Who Should Get Genetic Testing for Ovarian Cancer?

Guidelines from major medical organizations — including ASCO, the Society of Gynecologic Oncology, and the National Comprehensive Cancer Network — are clear: anyone diagnosed with epithelial ovarian cancer should receive genetic counseling and testing, regardless of age or family history.

But genetic testing isn’t only for people who have already been diagnosed.

You should also consider genetic ovarian cancer testing if you have:

• A strong family history of breast and ovarian cancers
• A moderate family history combined with Ashkenazi or Eastern European Jewish ancestry
• A personal history of breast cancer before age 50
• Male relatives with breast cancer
• A known BRCA mutation in a family member
• A triple-negative breast cancer diagnosis
• Pancreatic cancer in a first-degree relative
• A family history of colorectal or endometrial cancer, which may indicate Lynch syndrome risk

Beyond family history, certain communities carry a higher baseline risk. People from an Ashkenazi Jewish background are about five times more likely to carry a BRCA1 or BRCA2 variant compared to the general population. Similar elevated prevalence has been documented in Sephardi Jewish and Greenlander communities.

One thing many people don’t realize: men can carry and pass on these mutations, too. A father with a BRCA mutation has a 50% chance of passing it to each child, regardless of that child’s sex.

How Does Genetic Testing for Ovarian Cancer Work?

Genetic ovarian cancer testing typically involves a blood or saliva sample analyzed for mutations in genes known to increase ovarian cancer risk. Testing can be done in a laboratory, doctor’s office, hospital, or clinic. Results typically take several weeks.

The test itself isn’t complicated. What matters is understanding what the results mean. And that’s where genetic counseling becomes essential.

Types of Genetic Tests Available

Single-gene testing focuses on specific genes like BRCA1 or BRCA2 when a family mutation is already known.

Multigene panel testing screens for variants across all relevant genes simultaneously, and is now often available at similar cost to single-gene testing. This is generally preferred when family history suggests hereditary cancer but no specific mutation has been identified.

Comprehensive cancer panels examine genes associated with multiple cancer types.

A note on where to start: If an affected family member is available, testing them first is usually the most efficient path. Identifying the specific variant means at-risk relatives can then undergo targeted testing for that exact mutation rather than a broad panel. If no affected relative is available, multigene panel testing is typically the next best option, and many labs now offer these panels as a standard option.

Understanding Your Genetic Test Results

Getting tested is step one. Understanding what comes back is where things get more nuanced.

Positive result: A pathogenic variant was found. This means you carry a mutation known to increase ovarian cancer risk. 

Your parents, siblings, and children each have approximately a 50% chance of carrying the same mutation. If they decide to get tested, their test should specifically check for the variant you carry.

Negative result: No mutation was detected. But this doesn’t always mean zero elevated risk, especially if cancer runs in your family. A negative result on a direct-to-consumer test does not rule out other genetic mutations not included in that test. 

Always discuss negative results with a doctor or genetic counselor if you have a significant family history.

Variant of Uncertain Significance (VUS): The test found a change in a gene, but researchers don’t yet know whether it causes harm. This is more common than people expect, and it can feel frustrating. A genetics professional can help you understand what a VUS means in your specific context.

It’s also important to understand that genetic risk is not the whole story. Environmental and lifestyle factors — including age, reproductive history, and hormone use — can influence ovarian cancer risk as well. And even without any known germline mutation or identifiable risk factor, ovarian cancer can still occur.  

How Germline Mutations Affect Treatment Decisions

For people already diagnosed, genetic testing isn’t just about family risk. It has direct implications for treatment.

Knowing your germline mutation status helps your oncologist choose the most effective approach. The clearest example is PARP inhibitors: a class of drugs that have shown significant benefit in clinical trials for patients with BRCA1/2 pathogenic variants and HR-deficient tumors.

PARP inhibitors like olaparib, niraparib, and rucaparib are approved for maintenance therapy in high-grade epithelial ovarian cancers with BRCA mutations, and have shown meaningful improvements in progression-free survival. 

It’s worth noting that these treatments are generally less effective for low-grade serous ovarian cancer (LGSOC), which has its own distinct treatment landscape. 

Emerging research also suggests promise for immunotherapy combinations in certain mutation-positive cancers, an area worth watching.

For women with BRCA mutations who haven’t yet been diagnosed, risk-reducing bilateral salpingo-oophorectomy (BSO) — the surgical removal of the ovaries and fallopian tubes — can reduce ovarian cancer risk by up to 96% and is generally recommended after the completion of childbearing. Learn more about oophorectomy surgery and what to expect.

The Disparity Problem in Genetic Ovarian Cancer Testing

One of the most troubling realities in ovarian cancer care is that access to genetic testing is not equal.

Research shows that genetic counseling was completed by 43% of White patients, 24% of Black patients, and 23% of Asian patients. Genetic testing completion rates follow a similar pattern: 40% for White patients, 26% for Black patients, and 14% for Asian patients. Uninsured patients are significantly less likely to complete testing than those with private insurance.

These are not small gaps. They represent real people who don’t have access to information that could save their lives or the lives of their families.

Studies suggest that implicit bias plays a role, with Hispanic and Black patients consistently less likely to be referred for genetic counseling. And yet data show that pathogenic BRCA variants are prevalent across racial and ethnic groups, not just in communities where testing has historically been concentrated. Addressing this disparity isn’t optional. It’s urgent.

At-Home and Lower-Cost Testing Options

The Ovarian Cancer Research Alliance (OCRA) offers a free at-home genetic testing program for eligible individuals. The test screens for BRCA mutations, Lynch syndrome, and other variants linked to inherited risk of ovarian, uterine, breast, colorectal, and prostate cancers. Genetic counselors are available to help interpret results.

Direct-to-consumer genetic tests are also available without a prescription, but they typically screen for only a limited number of variants. 

The FDA-approved direct-to-consumer BRCA test, for example, looks for just 3 out of more than 1,000 known BRCA variants. These tests can be a useful starting point, but they’re not a definitive answer. Always discuss results with a doctor or genetic counselor, particularly if you have a meaningful family history.

What Happens After a Positive Genetic Test?

A positive result can feel overwhelming. But it also opens doors.

Depending on your specific mutation and situation, options may include:

• Increased surveillance, such as regular imaging and CA-125 blood tests
• Risk-reducing surgery, including salpingo-oophorectomy (removal of the ovaries and fallopian tubes)
• Preventive medications, including oral contraceptives, which have been associated with reduced ovarian cancer risk in some populations and can reduce risk by up to 50% in BRCA carriers
• Fertility-sparing options, if you haven’t yet completed your family

You’ll also want to inform blood relatives so they can consider testing themselves. This process, called cascade testing, is one of the most powerful things a positive result can lead to. One confirmed mutation in a family can prompt testing that identifies multiple at-risk relatives, creating opportunities for prevention across generations.

Should You See a Genetic Counselor?

Yes, ideally before and after testing.

A genetic counselor is trained to assess your personal and family history, identify which tests make sense for you, explain what results actually mean, and help you build an action plan. They’re not just there to deliver results. They’re there to help you understand them.

If ovarian cancer runs in your family, or if you’ve already been diagnosed, ask your gynecologic oncologist for a referral.

The Bottom Line on Germline Mutations and Ovarian Cancer

Germline mutations don’t determine your destiny. They inform your strategy.

Ovarian cancer is hard to catch early. There’s no perfect early detection method. Symptoms are easy to miss. But genetic testing for ovarian cancer is one concrete, evidence-backed tool that can genuinely change the trajectory of this disease — for individuals and for families.

If you’ve been diagnosed with ovarian cancer, genetic testing should be part of your care. Full stop. If you haven’t been diagnosed but have a family history, Ashkenazi Jewish ancestry, or a known mutation in your family, it’s worth having a conversation with your doctor. And if cost or access has been a barrier, programs like OCRA’s free testing initiative exist precisely to remove that obstacle.

At Not These Ovaries, we believe that action and understanding save lives. Knowing your genetic status is one of the most powerful forms of both.