Hereditary breast and ovarian cancer syndrome (BRCA1, BRCA2)

Hereditary breast and ovarian cancer syndrome is an inherited condition that raises the lifetime risk of several cancers, most importantly breast cancer and ovarian cancer. It is caused by a change in one of two genes, BRCA1 or BRCA2. It is often shortened to HBOC.

Roughly 1 in 400 people carries a change in one of these genes, and the figure is far higher in some populations, approaching 1 in 40 among people of Ashkenazi Jewish ancestry. Most carriers do not know.

This syndrome affects men as well as women, and men are frequently overlooked. A man carrying a BRCA change has meaningfully raised risks of his own, particularly of prostate cancer, and he passes the change to his children at exactly the same rate a woman does.

Unlike most hereditary cancer syndromes, this one also has targeted drugs attached to it. A class of medicines called PARP inhibitors works specifically against cancers arising in BRCA carriers, so a positive result can change treatment as well as risk management.

This article is written both for people diagnosed with a cancer linked to this syndrome and for people who carry a gene change without having had cancer, often identified after a relative was tested. If you are in the second group, most of what follows is about prevention.

What do the BRCA1 and BRCA2 genes do?

Despite their names, BRCA1 and BRCA2 are not “breast cancer genes” in the sense of causing cancer. They are repair genes, and they do essential work in every cell of the body.

DNA is occasionally broken clean through, both strands severed at once. This is the most dangerous kind of damage a cell can sustain. BRCA1 and BRCA2 are central to the system that repairs these breaks accurately, called homologous recombination, which uses the matching chromosome as a template so the repair is faithful rather than approximate.

Both are tumor suppressor genes, and everyone carries two copies of each. A person with this syndrome is born with one working copy and one that does not work. That single working copy is enough for normal life. If it is damaged in any individual cell over a lifetime, that cell loses accurate repair and must fall back on a sloppier backup system. Damage then accumulates, and the cell can become cancerous. Breast and ovarian tissue appear particularly vulnerable, though the reasons are not fully understood.

This same biology is why PARP inhibitors work. PARP is part of the backup repair system a BRCA-deficient cancer cell has come to depend on. Blocking it removes the cell’s remaining repair option while healthy cells, which still have one working BRCA copy, carry on. The drug exploits the cancer’s own weakness.

Cancers associated with hereditary breast and ovarian cancer syndrome

The figures below are cumulative risks to about age 80, with the general population risk alongside for comparison. Risks differ between the two genes, and where the difference is large it is given separately.

Breast cancer in women

Lifetime risk of breast cancer is approximately 72% for BRCA1 carriers and 69% for BRCA2 carriers, compared with about 13% in the general population. Risk begins rising in the late twenties and climbs steeply through the thirties and forties, which is why surveillance starts far earlier than routine mammography.

A woman who has already had one breast cancer faces a substantial risk of a second, separate cancer in the other breast: roughly 40% for BRCA1 and 26% for BRCA2 within twenty years of the first diagnosis. This risk is a major reason surgical decisions at the time of a first diagnosis are approached differently in carriers.

The two genes tend to produce different tumors. BRCA1 breast cancers are most often triple-negative, meaning they lack the estrogen receptor, the progesterone receptor, and HER2, and they are usually high grade. BRCA2 breast cancers are more often estrogen receptor positive. This matters because treatment follows the receptor results, and because a young woman with triple-negative breast cancer is offered genetic testing on that basis alone.

Ovarian, fallopian tube, and peritoneal cancer

Lifetime risk is approximately 44% for BRCA1 and 17% for BRCA2, compared with about 1% in the general population. This is the largest difference between the two genes and it directly affects the timing of preventive surgery.

These three cancers are grouped together because they are now understood to be one disease. Most high-grade serous carcinomas, the type that predominates in this syndrome, begin in the fimbrial end of the fallopian tube rather than in the ovary itself, and spread from there. This is why preventive surgery always removes the fallopian tubes and why the tubes are examined in fine detail by the pathologist afterward.

Onset is earlier than in the general population, typically from the mid-forties for BRCA1 carriers and later for BRCA2.

Breast cancer in men

Lifetime risk is approximately 7% to 8% for BRCA2 carriers and around 1% for BRCA1, compared with roughly 0.1% for men in the general population. In relative terms, this is a very large increase, though the absolute risk remains modest. Male breast cancer is frequently diagnosed late because neither the man nor his doctor considers it.

Prostate cancer

Lifetime risk for BRCA2 carriers is approximately 27% by age 80, rising further with age, compared with roughly 11% to 13% in the general population. BRCA1 carriers have a more modest increase. Beyond frequency, BRCA2-associated prostate cancers tend to be diagnosed younger, to be higher grade, and to behave less favorably than sporadic prostate cancers, which is why screening is offered earlier to carriers.

Pancreatic cancer

Lifetime risk is approximately 3% to 5% for BRCA2 carriers and around 2% to 3% for BRCA1, compared with about 1.7% in the general population. The increase is real but modest, and surveillance is generally reserved for carriers who also have a family history of pancreatic cancer.

Other cancers

A modestly increased risk of stomach cancer has been shown for both genes in recent prospective work, and BRCA2 carriers have a small increase in melanoma risk. Beyond these, large studies have not found meaningful increases for other cancer types. Carriers often assume every cancer in the family must be connected, and for the most part it is not.

How lifetime risk is estimated and why the numbers vary

Published risk figures for this syndrome vary widely, and understanding why makes them usable.

The earliest estimates came from families identified precisely because many members had cancer across several generations. Such families are selected for having a lot of cancer, so those studies overstate risk for the average carrier. Later work followed thousands of carriers forward in time regardless of family history, and produced the figures used in this article, which are lower than the older ones but still high.

Even within these better estimates, an individual’s risk is not a single number. Three things shift it:

Family history — A carrier with several close relatives affected at young ages faces a higher risk than a carrier found incidentally in a family with little cancer. This is one of the strongest modifiers, and it is why the same variant can carry different practical implications in different families.
Where in the gene the change sits — Certain regions of BRCA1 and BRCA2 are associated with relatively higher ovarian and lower breast cancer risk, and others the reverse. This is not yet used to set surveillance schedules for most people, but it is one reason estimates differ.
Other genetic and lifestyle factors — Many common genetic variants each nudge risk slightly, and reproductive history and other factors contribute.

Finally, a high lifetime risk is not a certainty. Roughly three in ten BRCA1 carriers and a similar proportion of BRCA2 carriers never develop breast cancer, and the majority never develop ovarian cancer. That does not make the risk small, and it does not argue against prevention. It means the figures describe a group, and a genetics service can give an estimate that reflects your gene, your sex, and your own family.

Who should be tested?

Testing criteria have broadened considerably, and many people who would not have qualified a decade ago are now eligible. Genetic testing is generally offered when:

Breast cancer is diagnosed at or before age 50, or at any age if it is triple-negative, or occurs in both breasts, or occurs in a man.
Ovarian, fallopian tube, or primary peritoneal cancer is diagnosed at any age. Family history is not required.
Pancreatic cancer or metastatic prostate cancer is diagnosed at any age.
Several relatives on the same side of the family have had breast, ovarian, pancreatic, or prostate cancer.
A known gene change has already been identified in the family.
The person has Ashkenazi Jewish ancestry together with a personal or family history of a related cancer, because three specific founder variants are common in that population.

Founder variants also occur in Icelandic, Polish, French Canadian, Bahamian, and several other populations, where a small number of specific changes account for most cases. Your ancestry is useful information for a genetics service, even when the family history seems unremarkable.

How the test is performed

Germline testing is done on a blood or saliva sample and examines the DNA a person was born with. The analysis uses next generation sequencing to read the genes letter by letter, together with a separate method that detects large deletions and duplications, where whole sections of a gene are missing or repeated. Both are necessary: a meaningful share of BRCA1 changes are large rearrangements that sequencing alone will not find. Older or limited tests did not always include this step. If you were tested many years ago, ask whether your test covered large rearrangements and whether retesting would be useful.

BRCA1 and BRCA2 are now almost always tested as part of a panel covering many hereditary cancer genes at once. This means a result may name genes you were not expecting, including PALB2, ATM, CHEK2, and others that also affect breast cancer risk to varying degrees.

Separately, tumor tissue may be tested for BRCA changes and for a broader pattern called homologous recombination deficiency, which is used in ovarian cancer to predict benefit from PARP inhibitors. That is a test on the cancer rather than on inherited DNA, and it is covered in our article on homologous recombination deficiency in ovarian cancer.

How results are reported

Pathogenic or likely pathogenic variant — A change known, or strongly expected, to stop the gene working. This is a positive result and confirms the syndrome.
Variant of uncertain significance — A change was found, but there is not enough evidence to say whether it affects the gene. This is not a positive result and is not a basis for preventive surgery. It is managed as though the result were negative, with surveillance guided by family history. Most such variants are eventually reclassified as harmless. Reclassification is more common for people of non-European ancestry, simply because those populations are less well represented in the reference databases, so staying in contact with the genetics service particularly matters.
Benign or likely benign variant — A harmless difference in the gene.
No variant identified — No change was found in the genes tested.

What the result means

A pathogenic or likely pathogenic variant confirms the syndrome. Each of the person’s children, siblings, and parents has a 50% chance of carrying the same change, and this applies equally whether the carrier is a man or a woman.

A negative result means two different things depending on the situation:

True negative — A specific variant is already known in the family and you tested negative for that exact variant. You did not inherit it, your risk returns to roughly that of the general population, and your children cannot inherit it from you. Routine screening applies.
Uninformative negative — No variant has been identified in anyone in the family. This rules out the genes tested but does not rule out an inherited cause. Only a minority of families with a strong breast cancer history carry a BRCA change, and for the rest the cause is often a combination of many smaller genetic factors. Surveillance continues based on family history, and enhanced screening is frequently recommended despite the negative result.

A negative BRCA result in a family with a striking cancer history does not mean the family history has been explained away or that increased screening can stop.

Germline versus somatic BRCA changes

A germline change is present in the DNA a person was born with, exists in every cell, and can be passed to children. This is the hereditary syndrome.

A somatic change arises within a tumor during a person’s lifetime. It exists only in the cancer cells, cannot be inherited, and carries no implications for relatives.

This distinction matters unusually often in BRCA, because tumor sequencing is now routine in ovarian, prostate, and pancreatic cancer, and it detects both kinds. Roughly one in five ovarian cancers carries a BRCA change, and only about two thirds of those are inherited; the rest arose in the tumor alone. Both groups may benefit from PARP inhibitors, so the treatment implication can be the same while the family implication is entirely different.

If a tumor report has described a BRCA1 or BRCA2 mutation and nobody has discussed germline testing on a blood or saliva sample with you, you can ask whether it would be appropriate.

Surveillance and risk reduction

More is available for this syndrome than for most, and the options differ in how much risk they remove and what they cost the person. What follows is what care teams generally consider; the balance between these is individual.

Breast surveillance

For women, annual breast MRI generally begins at age 25, with annual mammography added from age 30, often alternating so that some imaging occurs every six months. MRI is used because it is considerably more sensitive than mammography in young women with dense breast tissue, and because the cancers in this syndrome can grow quickly between examinations. Surveillance finds cancers earlier; it does not prevent them.

Risk-reducing mastectomy

Removing both breasts before cancer develops reduces breast cancer risk by more than 90%. It is an elective, irreversible operation, usually with reconstruction, and it carries permanent consequences: loss of sensation in the chest, the possibility of further operations, effects on body image, and an inability to breastfeed. It is not a small decision and is not recommended universally. Many carriers choose intensive surveillance instead, and that is a legitimate choice; unlike ovarian cancer, breast cancer found on MRI surveillance is usually caught early and treated successfully.

Risk-reducing removal of the ovaries and fallopian tubes

Removing both ovaries and fallopian tubes reduces ovarian cancer risk by roughly 80% or more and is the only measure shown to reduce deaths in this syndrome. Guidelines generally suggest it at age 35 to 40 for BRCA1 carriers and 40 to 45 for BRCA2 carriers, after childbearing is complete, reflecting the different ages at which ovarian cancer risk rises for the two genes.

The consequences are substantial. It ends fertility. Performed before natural menopause, it causes immediate surgical menopause, with hot flashes, sleep disturbance, effects on sexual function, and long-term effects on bone and cardiovascular health that are more pronounced the younger the surgery. Hormone replacement therapy up to the age of natural menopause is generally considered appropriate for women without a history of breast cancer, and it substantially offsets these effects. Many carriers assume incorrectly that hormone therapy is closed to them, so ask your team directly whether it applies to you.

An approach of removing the fallopian tubes first and deferring removal of the ovaries until later is under active study, aiming to preserve hormonal function longer. It is not yet standard practice, and carriers interested in it are usually directed toward a clinical trial.

Ovarian cancer screening

There is no effective screening test for ovarian cancer. CA-125 blood testing and transvaginal ultrasound have been studied in large trials and do not reduce deaths, because the cancer spreads before the tests detect it. Some centers offer them to women who have not had surgery, with the honest caveat that they provide limited reassurance. This is the central reason risk-reducing surgery carries more weight for the ovaries than for the breasts.

Men

Men carrying a BRCA change are generally offered training in breast self-examination and an annual clinical breast examination from around age 35, and a discussion about PSA screening for prostate cancer from around age 40, particularly for BRCA2 carriers. Male carriers are frequently left out of family testing and surveillance.

Pancreatic surveillance

Surveillance with MRI and endoscopic ultrasound, usually from around age 50, is generally offered to carriers who also have a family history of pancreatic cancer, rather than to all carriers. It is done in specialized centers.

If cancer is diagnosed

A BRCA result changes treatment as well as risk management. PARP inhibitors, including olaparib, talazoparib, niraparib, and rucaparib, are approved across several cancers in carriers: as maintenance treatment in ovarian cancer, for advanced breast cancer, after chemotherapy in pancreatic cancer, and in advanced prostate cancer. In early breast cancer, adjuvant olaparib has been shown to improve both disease-free and overall survival for carriers with higher-risk HER2-negative disease. BRCA-related cancers also tend to respond particularly well to platinum chemotherapy.

The details differ by cancer type and are covered in our articles on BRCA1 and BRCA2 in breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer.

Testing family members

This syndrome is inherited in an autosomal dominant pattern, meaning a single altered copy of the gene is enough to cause it. Each child, sibling, and parent of a carrier has a 50% chance of carrying the same change.

The gene passes through fathers exactly as it does through mothers. A man who carries a BRCA change has a 50% chance of passing it to each of his daughters and sons. Families frequently assume that a condition causing breast and ovarian cancer must come from the mother’s side, and this assumption causes real harm, because it leads whole branches of families to conclude they are not at risk.

Once a specific variant is identified in one family member, relatives can be tested for that exact change through cascade testing, which is simpler, cheaper, and definitive.

Testing is usually offered to adults, commonly from around age 18 to 25, since surveillance does not begin before the mid-twenties. Genetics services routinely help with notifying relatives, including providing a letter that can be passed on.

Carriers planning a family sometimes ask whether the change can be avoided in their children. Reproductive options including preimplantation genetic testing, in which embryos created through IVF are tested before transfer, and prenatal testing, are available in many places. These raise practical and personal questions that a genetics service and a fertility specialist can work through together. Raise them early, because fertility planning interacts with the timing of preventive surgery.

What happens next

For someone newly diagnosed with a related cancer, the germline result may change surgical decisions, may open PARP inhibitor treatment, and triggers a surveillance plan for the other organs at risk and referral for family testing. Testing is usually arranged promptly at diagnosis for this reason rather than deferred.

For a carrier who has not had cancer, the work is preventive: establishing breast surveillance, working through the timing of risk-reducing surgery alongside plans for children, arranging the other surveillance appropriate to sex and family history, and arranging cascade testing for relatives.

Care is usually coordinated through a hereditary cancer clinic. Because decisions here are made young, unfold over decades, and involve fertility, body image, and menopause as much as cancer, most centers also offer psychological support and can connect people with carrier support organizations. Many carriers find that decisions they were not ready to make at 30 become clearer at 38, and revisiting the conversation periodically is normal rather than a failure to decide.

Questions to ask your doctor

Which gene is involved, and how does that change my risks and the timing of anything I might consider?
Was my result a pathogenic variant, or a variant of uncertain significance?
Did the testing look for large deletions and duplications as well as sequence changes?
Based on my gene, my sex, and my family history, what are my estimated lifetime risks?
When should my breast MRI and mammography start, and how will they be scheduled?
What are the arguments for and against risk-reducing mastectomy in my situation?
When should I consider having my ovaries and fallopian tubes removed, and how does that fit with my plans for children?
If I have that surgery before menopause, would hormone replacement therapy be appropriate for me?
Is there any useful screening for ovarian cancer while I wait?
If I am a man, what surveillance applies to me, and when should prostate screening start?
Should I have pancreatic surveillance, given my family history?
If I have cancer now, does this result change my treatment or make me eligible for a PARP inhibitor?
Which of my relatives should be offered testing, including on my father’s side, and can you provide a letter for them?
What reproductive options are available if I want to avoid passing this on?
Is psychological support or a support group available to help me work through these decisions?