Hereditary Ovarian Cancer: Risk Genes, Family History, Testing, Prevention, and Treatment

Hereditary ovarian cancer is ovarian, fallopian tube, or primary peritoneal cancer, the risk of which is increased due to an inherited pathogenic variant in a cancer predisposition gene. This variant is present in all cells of the body from birth, can be passed on to children, and is important not only for the patient but also for her relatives. [1]

In modern gynecologic oncology, ovarian cancer, fallopian tube cancer, and primary peritoneal cancer are often considered together because many highly malignant serous tumors, previously considered ovarian, can begin in the fallopian tube and then spread to the ovary and peritoneum. Therefore, hereditary risk is usually assessed not only for the "ovary" in the narrow sense, but for this entire group of tumors. [2]

The main hereditary causes are linked to the BRCA1 and BRCA2 genes, which are involved in repairing damage to deoxyribonucleic acid. When one of these genes malfunctions due to a pathogenic variant, cells are less able to repair dangerous damage, and the likelihood of tumor growth increases. [3]

In addition to BRCA1 and BRCA2, the risk of ovarian cancer may be increased by Lynch syndrome and pathogenic variants of other predisposition genes. Therefore, current guidelines recommend not only BRCA1 and BRCA2 testing but also broader genetic panels if clinically justified. [4]

Hereditary ovarian cancer does not necessarily mean that every mutation carrier will develop the disease. It does indicate an increased risk, requiring individualized prevention, appropriate treatment choices once diagnosed, and informed screening of relatives. [5]

Concept	What does it mean?	Why is it important?
Hereditary pathogenic variant	An inherited gene change that increases the risk of cancer	Can be transmitted to relatives
BRCA1 and BRCA2	Deoxyribonucleic acid damage repair genes	The most well-known hereditary risk genes
Lynch syndrome	Hereditary disorder of the deoxyribonucleic acid error-correction system	Increases the risk of endometrial, colon and ovarian cancer
Tumor testing	Tumor tissue analysis	Helps to choose treatment
Hereditary testing	Blood or saliva test	Shows the inherent risk to the patient and family
Family cascade screening	Testing relatives after detection of a mutation in the family	Helps prevent cancer in healthy carriers

Table source: US National Cancer Institute, GeneReviews, American Society of Clinical Oncology, and Society of Gynecologic Oncology. [6]

International Classification of Diseases codes of the 10th and 11th revisions

In the International Classification of Diseases, 10th revision, ovarian cancer itself is coded as malignant neoplasm of the ovary in group C56. If the cancer itself is not being treated, but rather a hereditary susceptibility to malignant tumors, separate codes for genetic predisposition may be used in clinical modifications, but the specific entry depends on the country and the version of the classifier used. [7]

It's important to understand that the ovarian cancer code does not indicate whether the tumor is hereditary. For this purpose, the medical records separately indicate the results of genetic testing, such as the pathogenic variant of BRCA1, BRCA2, or another gene, as well as the tumor's morphological type and stage. [8]

System	Code or heading	Formulation	Practical meaning
ICD 10	C56	Malignant neoplasm of the ovary	Ovarian cancer major code
ICD 10, clinical modification	C56.1	Malignant neoplasm of the right ovary	Clarification of the party
ICD 10, clinical modification	C56.2	Malignant neoplasm of the left ovary	Clarification of the party
ICD 10, clinical modification	C56.3	Malignant neoplasm of both ovaries	Bilateral defeat
ICD 10, clinical modification	Z15.01 and Z15.02	Genetic susceptibility to breast or ovarian cancer	Reflects hereditary risk
ICD 11	2C73	Malignant neoplasms of the ovary	Basic ovarian cancer rubric
ICD 11	2C73.0	Ovarian carcinomas	Epithelial carcinomas

Table source: Reference data on ovarian cancer coding and hereditary cancer risk, as well as recommendations for genetic testing. [9]

In the International Classification of Diseases, 11th revision, malignant ovarian tumors are classified under category 2C73. This category helps code the tumor itself, but does not replace a genetic diagnosis, because hereditary status influences treatment, prevention, and screening of relatives. [10]

If a patient is diagnosed with a pathogenic variant of BRCA1, BRCA2, or another gene, this should be reflected in the clinical diagnosis or a separate genetic report. For the oncologist, this information can be as important as the stage, as it influences the choice of maintenance therapy, the risk of a second cancer, and family counseling. [11]

Major genetic risk genes

The BRCA1 and BRCA2 genes are the most well-known and clinically significant genes for hereditary ovarian cancer. According to the US National Cancer Institute, harmful changes in these genes significantly increase the risk of breast and ovarian cancer, and are also associated with fallopian tube cancer and primary peritoneal cancer. [12]

The risk for BRCA1 is generally higher and appears earlier than for BRCA2. The US National Cancer Institute provides estimated lifetime risks of ovarian, fallopian tube, or primary peritoneal cancer: approximately 39-58% for women with a harmful BRCA1 variant and approximately 13-29% for women with a harmful BRCA2 variant. [13]

BRCA1 and BRCA2 are important not only for risk assessment. In established epithelial ovarian cancer, the presence of hereditary or tumor-associated alterations in these genes can influence sensitivity to platinum-based drugs and the ability to use polyadenosine diphosphate-ribose polymerase inhibitors. [14]

Lynch syndrome is associated with genes in the deoxyribonucleic acid mismatch repair system. It is most often associated with colon and endometrial cancer, but may also increase the risk of ovarian cancer, particularly certain non-serous subtypes. [15]

In addition to these syndromes, clinical panels may evaluate RAD51C, RAD51D, BRIP1, PALB2, and other genes if consistent with family history or tumor type. Such results should be interpreted by a specialist, as not every identified variant is pathogenic, and not every gene carries the same risk. [16]

Gene or syndrome	Link to ovarian cancer	What is important in practice
BRCA1	One of the highest hereditary risks	Prophylactic removal of the fallopian tubes and ovaries after the completion of reproductive plans is often discussed.
BRCA2	The risk is lower than with BRCA1, but significantly higher than the population risk.	Prevention, treatment and examination of relatives are important
Lynch syndrome	Increases the risk of ovarian, endometrial, and colon cancer	A multi-organ monitoring plan is needed
RAD51C	Increases the risk of ovarian cancer	May influence preventive strategy
RAD51D	Increases the risk of ovarian cancer	Requires genetic counseling
BRIP1	Linked to increased risk of ovarian cancer	Usually not equal to BRCA1 risk
PALB2	Better known for breast cancer risk, but may be considered in panels	Interpretation depends on family history

Table source: American Society of Clinical Oncology, Society of Gynecologic Oncology, GeneReviews, and National Cancer Institute. [17]

Who needs genetic testing?

The current principle is simple: all patients with epithelial ovarian cancer should be offered hereditary genetic testing. The American Society of Clinical Oncology recommends testing for BRCA1, BRCA2, and other ovarian cancer predisposition genes for all women with epithelial ovarian cancer, regardless of age and family history. [18]

The Society of Gynecologic Oncology also recommends offering hereditary testing to all patients with epithelial ovarian cancer in its 2024 clinical statement. The statement specifically emphasizes that universal testing is important, but in practice, it is hampered by resource constraints, heterogeneity of practice, and inequality of access. [19]

If hereditary testing does not reveal a pathogenic BRCA1 or BRCA2 variant, tumor testing may still be helpful. ASCO recommends tumor testing for BRCA1 and BRCA2 in women with epithelial ovarian cancer if an hereditary pathogenic variant is not found, because the change may be tumor-specific and impact treatment. [20]

Healthy relatives are typically offered testing not at random, but after a specific pathogenic variant has been identified in the family. If a patient is found to have a hereditary variant, first-degree relatives have a 50% chance of being carriers of the same variant, so they are recommended to undergo genetic counseling and targeted testing. [21]

Genetic testing should be accompanied by counseling. The meaning of a pathogenic variant, a likely pathogenic variant, a benign variant, and a variant of uncertain significance should be explained to the individual, as misinterpretation can lead to either false reassurance or excessive preventive interventions. [22]

Who is especially recommended for testing?	What test are they discussing?	Why
All patients with epithelial ovarian cancer	Genetic panel with BRCA1, BRCA2 and other genes	The result affects treatment and relatives
Patients without hereditary BRCA1 or BRCA2	Tumor testing for BRCA1 and BRCA2	May reveal somatic changes
Patients with clear cell, endometrioid or mucinous subtype	Evaluation of a mating error correction system based on indications	Possible connection with Lynch syndrome
Healthy relatives of a mutation carrier	Targeted testing of the identified family variant	Allows you to determine your personal risk
Families with ovarian, breast, pancreatic, and prostate cancer	Genetic counseling	A hereditary syndrome is possible
People with a variant of indefinite meaning	Observation without radical decisions only for this option	This variant is not equal to a proven mutation.

Table source: ASCO, SGO, GeneReviews, and NCCN patient guidelines for hereditary risk.[23]

How genetic findings impact treatment

In established epithelial ovarian cancer, genetic testing influences not only the prognosis but also the choice of drug therapy. Pathogenic variants of BRCA1 and BRCA2, as well as tumor features of homologous recombination deficiency, may indicate increased tumor sensitivity to drugs that damage deoxyribonucleic acid and to polyadenosine diphosphate-ribose polymerase inhibitors. [24]

A distinction is made between hereditary and somatic results. The hereditary variant is found in blood or saliva and is important for the entire family, while the somatic variant is found only in tumor tissue and is usually not passed on to children. Both results can be important for treatment, but only the hereditary result automatically requires cascade testing of relatives. [25]

If a patient is diagnosed with a hereditary pathogenic BRCA1 or BRCA2 variant, the doctor discusses not only the treatment of the current ovarian cancer but also the risk of breast cancer, pancreatic cancer, and other BRCA-associated tumors. Therefore, a separate monitoring or prevention program for other organs may be necessary after cancer treatment. [26]

In Lynch syndrome, a different spectrum of risks is important. The patient and relatives may require monitoring of the colon, endometrium, and other organs, and tumor testing for mating error correction defects may influence the choice of immunotherapy in certain clinical situations. [27]

A negative test result does not mean the cancer is 100% "not hereditary." Sometimes the cause remains unknown, the test may have missed a rare gene, or the familial risk may be polygenic or linked to as-yet-unidentified variants; therefore, family history remains an important part of the evaluation. [28]

Result	What does it mean?	How does it affect tactics?
Hereditary pathogenic variant of BRCA1	High congenital risk of BRCA-associated tumors	Affects treatment, prevention and relatives
Hereditary pathogenic variant of BRCA2	Increased risk of ovarian, breast and other cancers	Affects treatment and family testing
Somatic BRCA1 or BRCA2 mutation	Change found in tumor	May affect therapy, but usually does not mean risk to relatives
Homologous recombination deficiency	Tumors are less able to repair damage to deoxyribonucleic acid	May help guide supportive treatment choices
Mating error correction system defect	Possible Lynch syndrome or tumor defect	May influence genetics and therapy
Variant of indefinite value	The meaning is still unknown	Should not in itself lead to prophylactic surgery

Table source: ASCO, SGO, GeneReviews, and National Cancer Institute. [29]

Prevention in high-risk carriers

The most effective preventive measure for women with pathogenic BRCA1 or BRCA2 variants is risk-reducing removal of the fallopian tubes and ovaries after reproductive plans are complete. This surgery reduces the risk of ovarian, fallopian tube, and primary peritoneal cancer, but does not eliminate it completely, because primary peritoneal cancer remains a possibility. [30]

The timing of surgery is individualized and is usually linked to the gene type, family history, pregnancy plans, and risk of early menopause. With BRCA1, the risk of ovarian cancer typically begins to increase earlier than with BRCA2, so the timing of prophylactic surgery for BRCA1 carriers is often discussed earlier. [31]

Surgical menopause occurs after ovarian removal before natural menopause. This can impact hot flashes, sleep, mood, sexual function, bone density, and cardiovascular risk, so preventative care should include a discussion of quality of life, hormone replacement therapy (HRT) if appropriate, fertility preservation, and individual contraindications. [32]

Tubal ablation with delayed ovarian ablation is being explored as a possible strategy, as many serous tumors can originate in the fallopian tubes. However, for women with a high hereditary risk, this strategy should not yet automatically replace proven risk-reducing surgery unless a separate decision is made through specialized surveillance or research. [33]

Oral contraceptives may reduce the risk of ovarian cancer, but in women with a hereditary risk, their use should be discussed individually. The physician considers the patient's age, contraindications, risk of thrombosis, risk of breast cancer, reproductive plans, and preferences. [34]

Preventive measure	For whom is it relevant?	Restrictions
Risk-reducing removal of the fallopian tubes and ovaries	Carriers of BRCA1, BRCA2 and some other high-risk genes	Early menopause and its impact on quality of life
Genetic counseling	Patients and relatives	Requires correct interpretation of the result
Cascade testing of relatives	Families with a pathogenic variant found	Need a well-known family option
Oral contraceptives	Women without contraindications after medical assessment	Do not replace surgery in high-risk situations
Breast monitoring	BRCA1 and BRCA2 carriers	Does not reduce ovarian risk, but is important for other risks
Refusal of preventive surgery	Possible as a conscious decision of the patient	Requires an understanding of residual risk

Table source: US National Cancer Institute, GeneReviews, and NCCN Guidelines for Patients. [35]

Observation and screening

For women at average risk, routine ovarian cancer screening with transvaginal ultrasound and cancer antigen 125 has not been shown to reduce mortality. This is important because frequent screening and ultrasound can produce false-positive results and lead to unnecessary surgeries. [36]

For women with a high hereditary risk, the situation is more complex. Even among BRCA1 or BRCA2 carriers, ovarian cancer screening is not considered a reliable substitute for preventive surgery, because early detection of serous cancer remains difficult. [37]

If a high-risk carrier temporarily postpones prophylactic surgery, the physician may discuss individualized surveillance with cancer antigen 125 and transvaginal ultrasound. However, such surveillance should be viewed as a compromise, not as a proven, equivalent preventative measure. [38]

Breast monitoring is especially important for those with BRCA1 and BRCA2. Carriers of these variants have an increased risk of breast cancer, so they may be recommended to undergo breast magnetic resonance imaging (MRI), mammography, and discussion of preventive measures according to specific protocols. [39]

Better surveillance begins with accurate knowledge of the family variant. If a woman knows that a specific pathogenic mutation runs in her family, testing can differentiate relatives into carriers and noncarriers; this helps avoid both under- and over-surveillance. [40]

Situation	What is usually discussed	Important disclaimer
Average risk without symptoms	Routine screening is not recommended.	There is no proven reduction in mortality.
BRCA1 or BRCA2 before prophylactic surgery	Individual monitoring by physician's decision	Does not replace risk-reducing surgery
After risk-reducing surgery	Symptom control and general observation	Residual risk of primary peritoneal cancer remains
Lynch syndrome	Monitoring of the colon and endometrium according to the protocol	The risk affects several organs
Relatives of the carrier	Targeted testing of the family variant	Non-carriers generally do not require a high-risk program
Variant of indefinite value	Monitoring personal and family risk	Do not consider a high-risk option

Table source: NCI, GeneReviews, and NCCN Guidelines for Patients. [41]

What should relatives do?

If a patient with ovarian cancer is diagnosed with an inherited pathogenic variant, it has implications for the entire family. First-degree relatives—children, parents, and siblings—are typically offered genetic counseling and targeted testing specifically for the identified familial variant. [42]

If a relative has not inherited a familial pathogenic variant, their risk for that particular inherited syndrome typically reverts closer to the population level, although personal risk factors are still taken into account. If a variant is found, the individual receives a personalized prevention and surveillance plan. [43]

Men can also carry BRCA1 or BRCA2 and pass the variant on to their children. In men, these variants can increase the risk of prostate cancer, pancreatic cancer, and male breast cancer, so hereditary ovarian cancer is not just a "women's" family problem. [44]

It's important not to test everyone indiscriminately using broad panels without a plan, but to start with an infected relative, if possible. When the specific pathogenic variant in a patient is known, testing of relatives becomes more accurate, faster, and more straightforward. [45]

The psychological aspect is also important. A genetic result can cause anxiety, guilt, fear for children, and difficult decisions about preventive surgery; therefore, genetic counseling should include an explanation of the risks, preventive options, and the individual's right to make a decision gradually. [46]

Relative	Probability of carriage of the pathogenic variant in a patient	What is usually offered
Daughter or son	50%	Genetic counseling and targeted testing in adulthood
Sister or brother	Up to 50% if the variant is inherited from one of the parents	Targeted testing
Mother or father	May be a carrier if the variant is hereditary	Testing helps to understand the line of inheritance
Aunt, uncle, cousins	Depends on the family line	Testing after determining the family branch
Male carrier	Can pass the variant on to children	Surveillance for male BRCA-associated risks
Non-carrier of the family variant	Usually there is no increased risk for this particular variant.	Standard prevention based on age and personal factors

Table source: GeneReviews, National Cancer Institute, and NCCN Guidelines for Patients. [47]

Frequently asked questions

Is hereditary ovarian cancer always linked to only BRCA1 and BRCA2? No. BRCA1 and BRCA2 are the main and best-known genes, but the risk may also be associated with Lynch syndrome and other genes, including RAD51C, RAD51D, BRIP1, and some other predisposition genes. [48]

If there is no family history of ovarian cancer, should a patient diagnosed with ovarian cancer be tested? Yes. ASCO recommends hereditary genetic testing for all women with epithelial ovarian cancer, regardless of family history, because a hereditary variant can be identified even without an obvious family history. [49]

What is the risk of ovarian cancer with BRCA1 and BRCA2? The US National Cancer Institute lists estimated lifetime risks of ovarian, fallopian tube, or primary peritoneal cancer: about 39-58% with BRCA1 and about 13-29% with BRCA2. [50]

Does a negative BRCA1 and BRCA2 result completely rule out a hereditary cause? No. There may be another gene, a variant outside the capabilities of a specific test, or a familial risk without a detected mutation, so the result should be interpreted with a genetic counselor. [51]

What is a variant of uncertain significance? This is a genetic variant for which it is not yet known whether it increases the risk of cancer. This result cannot be used to make the same decisions as a proven pathogenic variant. [52]

Can ultrasound and cancer antigen 125 testing replace prophylactic surgery? For high-risk women, these methods are not considered an equivalent replacement for risk-reducing tubal and ovarian removal because early detection of ovarian cancer remains difficult. [53]

Why are both fallopian tubes and ovaries removed? Many high-grade serous tumors can begin in the fallopian tube, and the ovaries remain an important risk site; therefore, standard risk-reducing surgery usually includes both organs. [54]

Is there a residual risk after prophylactic removal of the fallopian tubes and ovaries? Yes, a small residual risk of primary peritoneal cancer remains, so surgery significantly reduces the risk, but does not eliminate it. [55]

Should men in the family be tested? Yes, if a hereditary pathogenic variant is found in the family, men may be carriers, pass the variant on to their children, and have their own BRCA-associated risks, including prostate and pancreatic cancer. [56]

How do genetics influence treatment of already diagnosed cancer? Results of BRCA1, BRCA2, and tumor testing can influence the choice of supportive therapy, including polyadenosine diphosphate-ribose polymerase inhibitors, as well as the plan for prevention and screening of relatives. [57]

Key points from experts

Panagiotis A. Konstantinopoulos, MD, an oncologist, is the lead author of the American Society of Clinical Oncology guideline on hereditary and tumor testing in epithelial ovarian cancer. Key message: All women with epithelial ovarian cancer should be offered hereditary testing for BRCA1, BRCA2, and other predisposition genes, and in the absence of a hereditary BRCA variant, tumor testing for BRCA1 and BRCA2 should be considered. [58]

Gregory M. Gressel, MD, MS, FACG, co-author of the 2024 Society of Gynecologic Oncology clinical statement. Key message: Universal hereditary testing for epithelial ovarian cancer should be offered to all patients, but in real-world practice, systemic barriers, resource constraints, and social inequities limit access. [59]

Noah Kauff, MD, is a co-author of the GeneReviews paper on BRCA1 and BRCA2-associated hereditary breast and ovarian cancer. Key point: BRCA1 and BRCA2-associated syndrome includes not only breast and ovarian cancer, but also fallopian tube cancer, primary peritoneal cancer, and a number of other tumors, necessitating a family-based approach to risk. [60]

National Comprehensive Cancer Network Working Groups on Hereditary Risk of Breast, Ovarian, Pancreatic, and Prostate Cancer. Key message: Genetic evaluation should consider not only a single diagnosis but also the entire family history, including breast, ovarian, pancreatic, and prostate cancers in both family lines. [61]

National Cancer Institute, US National Cancer Institute. Key message: Harmful variants in BRCA1 and BRCA2 dramatically increase the risk of ovarian, fallopian tube, and primary peritoneal cancer, but knowing your genetic status allows for early discussions about prevention, treatment, and testing of relatives. [62]