Beyond BRCA1, BRCA2, and Lynch Syndrome: The Other Hereditary Cancer Genes Worth Knowing

By Amanda Shrewsbury, MS, CGC

When most people hear the words "cancer genetic testing," they think of the BRCA1 and BRCA2 genes, or of Lynch syndrome. The BRCA genes and the Lynch syndrome genes are the most well known, studied, and identified causes of inherited cancer risk. But they are not the whole story, and they have not been for some time.

Modern multigene panels routinely test 30 to 80 or more genes at once, and findings outside of BRCA1, BRCA2, and the Lynch syndrome genes have become a regular part of clinical practice. Some of these genes confer cancer risks that approach or even match BRCA2. Others fall into a middle category that meaningfully changes screening recommendations without rising to the same level. A handful are rare but carry such significant risk that recognizing them is essential. Whether you are exploring testing for the first time, you have a family member with an unfamiliar result, or you have a cancer diagnosis and received genetic testing results that left you with questions, this post is for you.

What is the difference between a hereditary cancer gene and a hereditary cancer syndrome?

A gene is a specific stretch of DNA that codes for a protein. A syndrome is a clinical pattern of cancer risk caused by pathogenic variants (DNA changes that increase cancer risk) in one or more genes.

This distinction matters because the names get used interchangeably in casual conversation, and they shouldn't be. Hereditary Breast and Ovarian Cancer (HBOC) syndrome is the syndrome most commonly associated with pathogenic variants in BRCA1 and BRCA2, though variants in some of the genes we will discuss below (like PALB2 and the RAD51 genes) can produce overlapping clinical patterns. Lynch syndrome is the clinical syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM (Lynch et al., 2015).

When a multigene panel comes back with a finding, the result names the gene, not the syndrome. Understanding the gene helps you and your genetic counselor interpret what that variant means for your screening, your treatment if you have been diagnosed, and your family.

What are the other hereditary cancer genes besides BRCA1, BRCA2, and the Lynch syndrome genes?

A modern hereditary cancer panel will test for a substantial list of genes, but a smaller core group accounts for most of the clinically actionable findings outside of BRCA1, BRCA2, and the Lynch syndrome genes. The most commonly encountered include PALB2, CHEK2, ATM, RAD51C, RAD51D, BRIP1, and BARD1. A second group is rarer but carries significant clinical weight: TP53, PTEN, CDH1, and STK11.

We will walk through each one below.

What is the difference between high-penetrance and moderate-penetrance cancer genes?

Penetrance describes the likelihood that a person carrying a pathogenic variant will actually develop the associated cancer in their lifetime. High-penetrance genes (meaning a single variant in the gene confers a substantially elevated lifetime cancer risk, typically above 30 to 40 percent for the primary cancer type) drive the most striking risk profiles. Moderate-penetrance genes sit in a middle range, often roughly 15 to 30 percent lifetime risk depending on the cancer and the modifying factors involved.

The line between these categories is not fixed. As more population-based data accumulates, gene classifications shift. PALB2 is the clearest recent example. It was historically called a moderate-penetrance gene, but the largest studies now show breast cancer risks that approach BRCA2 territory, and many guidelines have moved to manage it similarly (Yang et al., 2020).

This is part of why working with a genetic counselor matters. The numbers we use to talk about risk are estimates that get refined as the science matures.

What is PALB2, and how does it affect cancer risk?

PALB2 stands for "Partner and Localizer of BRCA2," which is exactly what it does in the cell. It binds to the BRCA2 protein and helps it repair damaged DNA. When PALB2 is not working properly, BRCA2 cannot do its job as effectively, and the result is an inherited cancer risk profile that looks a lot like BRCA2's.

The cumulative breast cancer risk for women with a PALB2 pathogenic variant is estimated at roughly 33 to 53 percent by age 80, depending on family history, with the most-cited large international study placing the overall risk at 53 percent (95% CI, 44% to 63%) (Yang et al., 2020). Ovarian cancer risk is modestly elevated, in the 3 to 5 percent lifetime range. Pancreatic cancer risk is around 2 to 5 percent (National Cancer Institute, 2024). Male carriers face a modestly elevated risk of male breast cancer as well.

For these reasons, the National Comprehensive Cancer Network (NCCN) now manages PALB2 similarly to BRCA1 and BRCA2 in several important ways, including the recommendation for annual breast MRI in addition to mammography starting at age 30 (NCCN, 2025).

What is CHEK2, and what cancers is it linked to?

CHEK2 is a checkpoint gene. Its job is to pause the cell cycle when DNA damage is detected so that repair can happen before the cell divides. A pathogenic variant in CHEK2 means that this checkpoint does not function as reliably, and damaged cells are more likely to slip through.

The lifetime breast cancer risk for women with a pathogenic CHEK2 variant is estimated at roughly 20 to 33 percent by age 80, with the cumulative risk estimated at 33 percent (95% CI, 21% to 48%) in the largest population-based segregation analysis to date (Boonen et al., 2021). There are also smaller but real signals for colorectal and prostate cancer, and certain CHEK2 variants confer higher risk than others. The c.1100delC variant is particularly common in people of European ancestry as a founder variant, meaning it is inherited from a shared distant ancestor and recurs at higher rates in specific populations.

For most women with a pathogenic CHEK2 variant, lifetime breast cancer risk exceeds 20 percent, which is the threshold at which the American Cancer Society and American College of Radiology recommend annual breast MRI in addition to mammography (Saslow et al., 2007; Monticciolo et al., 2023).

What is ATM, and what does an ATM variant mean?

ATM stands for "Ataxia-Telangiectasia Mutated." It is another DNA damage response gene, and like CHEK2, it helps coordinate the cell's response to broken DNA. People who inherit one pathogenic ATM variant have an increased risk of certain cancers. People who inherit two copies (one from each parent) develop ataxia-telangiectasia, a rare and serious childhood condition that is separate from what we are discussing here.

For carriers of a single pathogenic ATM variant, lifetime breast cancer risk is estimated at roughly 20 to 30 percent, with risk varying by specific variant (Hu et al., 2021). Lifetime pancreatic cancer risk is approximately 5 to 10 percent, with the largest cohort study to date placing the cumulative risk at 9.5 percent (95% CI, 5.0% to 14.0%) by age 80 (Hsu et al., 2021). Newer evidence also supports an elevated prostate cancer risk for men (Hall et al., 2021). As with CHEK2, breast cancer risk in ATM carriers generally exceeds the 20 percent threshold that triggers high-risk screening recommendations.

What about the ovarian cancer cluster: RAD51C, RAD51D, and BRIP1?

These three genes share a common clinical thread: they primarily elevate the risk of ovarian cancer, with smaller signals for breast cancer in some of them. They are often grouped together because the management strategy is similar.

The estimated lifetime ovarian cancer risk by age 80 is approximately 11 percent for RAD51C carriers and 13 percent for RAD51D carriers. Lifetime breast cancer risk for these two genes is approximately 20 to 21 percent, with a particular signal for triple-negative breast cancer (Yang et al., 2020). BRIP1 carriers face an estimated 5 to 10 percent lifetime ovarian cancer risk, though some newer data suggests this may be an underestimate (Suszynska et al., 2020; Hanson et al., 2025).

Because ovarian cancer remains difficult to detect early, guidelines for these three genes typically recommend a discussion of risk-reducing salpingo-oophorectomy (surgical removal of the ovaries and fallopian tubes) between ages 45 and 50, depending on the gene and family history (Hanson et al., 2025). This is the kind of decision that benefits enormously from a thorough genetic counseling conversation, because the timing intersects with reproductive choices, hormone considerations, and personal values.

What about BARD1?

BARD1 stands for "BRCA1-Associated RING Domain 1," and like PALB2's relationship with BRCA2, BARD1 partners directly with BRCA1 in DNA repair. Its inclusion as a cancer risk gene has evolved over the last several years as the evidence has matured.

Current estimates place lifetime breast cancer risk for BARD1 carriers at roughly 17 to 30 percent, with a particularly strong signal for triple-negative breast cancer (Hu et al., 2021; NCCN, 2025). There is not currently a well-established ovarian cancer association, though research is ongoing. NCCN now recommends annual breast MRI in addition to mammography for BARD1 carriers starting at age 40, reflecting the strengthening evidence base.

What about the rare but high-impact genes: TP53, PTEN, CDH1, and STK11?

These genes are less commonly identified on panels, but a positive finding in any of them has major clinical implications. Each is associated with a recognized syndrome.

TP53 is associated with Li-Fraumeni syndrome, a condition characterized by very high lifetime cancer risk across multiple types, including sarcomas, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma. Lifetime cancer risk in classic Li-Fraumeni families approaches 70 percent or higher, with many cancers occurring in childhood and early adulthood (Mai et al., 2016). Newer data from panel testing in less selected populations suggests the average lifetime risk may be somewhat lower than the historical estimates, but it remains substantial.

PTEN is associated with PTEN hamartoma tumor syndrome, which includes Cowden syndrome. People with a PTEN pathogenic variant face an estimated 85 percent lifetime risk of developing any type of cancer. Breast cancer is the most common, with a lifetime risk of approximately 41 to 60 percent by age 80, along with elevated risks of thyroid (about 35 percent), endometrial (about 28 percent), kidney (up to 34 percent), and colorectal cancers (about 9 to 20 percent), and characteristic noncancer features (NCCN, 2025; National Cancer Institute, 2024).

CDH1 is associated with hereditary diffuse gastric cancer and lobular breast cancer syndrome. Lifetime risk of diffuse gastric cancer is estimated at roughly 25 to 33 percent for women and 37 to 42 percent for men, representing a meaningful refinement downward from earlier cohort-biased figures as multigene panel testing has expanded the populations studied (Roberts et al., 2019; NCCN, 2025). Women also carry roughly a 40 to 55 percent lifetime risk of lobular breast cancer (van der Post et al., 2015). Because diffuse gastric cancer is difficult to detect on endoscopy until late stages, prophylactic gastrectomy is often discussed as a risk-reduction option, though the decision is deeply personal and not the only path.

STK11 is associated with Peutz-Jeghers syndrome, which carries high cumulative risk for gastrointestinal, breast, gynecologic, and pancreatic cancers, often alongside characteristic mucocutaneous pigmentation that may be visible in childhood (Hearle et al., 2006).

These syndromes are rare, but recognizing them when they appear on a panel changes everything about subsequent management.

What does it mean if you have a variant in one of these genes?

A pathogenic variant is information, not a verdict. It tells you that your lifetime risk of certain cancers is higher than average, and it gives your clinical team a roadmap for screening, prevention, and in some cases treatment. It does not tell you that you will get cancer.

What management looks like depends on the gene, the specific variant, your age, your sex, your personal medical history, and your family history. The genes we have discussed each carry their own NCCN management guidelines that get updated as new evidence emerges. For someone who has already been diagnosed with cancer, a positive result may also change surgical decisions, eligibility for targeted therapies like PARP inhibitors, and recommendations for surveillance of second primary cancers.

A positive result also has implications for family members. First-degree relatives (parents, siblings, children) may have up to a 50 percent chance of carrying the same variant, and cascade testing (testing family members for a known variant) lets relatives learn whether the finding applies to them. Our post on how to talk to your family about genetic testing walks through that conversation in more detail.

Should you test for these genes if your family history is not strong?

Yes, in many cases. The conversation around testing criteria has changed substantially over the last decade. NCCN testing criteria are broader than many people realize, and growing data shows that meaningful numbers of pathogenic variants are found in people who would not meet the older, stricter family-history thresholds (Beitsch et al., 2019). If you are exploring testing for proactive or longevity reasons, this is part of what is on the table. If you have been recently diagnosed with cancer, panel testing is increasingly the standard of care regardless of family history.

A genetic counseling appointment is the most efficient way to figure out whether testing makes sense for you and which panel is appropriate. Our post on the 10 reasons to consider genetic testing for cancer covers the most common scenarios, and our walkthrough of what actually happens during a genetic counseling appointment shows what to expect if you book one.

A broader landscape than most people realize

After reading this, our hope is that it's clear that the hereditary cancer landscape is much broader than the few well known genes that come to mind. We can now analyze genes that we couldn't decades ago, and we have a much better understanding of what variants in these genes mean. This means that patients and families who didn't have answers previously, may now have them.

Have a question? Reach out anytime:

References

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This blog post is for educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always seek the advice of your physician, genetic counselor, or other qualified healthcare provider with any questions you may have regarding a medical condition or your individual health needs.