National Cancer Institute

Posted Date: Apr 27, 2014

Expert-reviewed information summary about the genetics of breast and ovarian cancer, including information about specific genes and family cancer syndromes. The summary also contains information about interventions that may influence the risk of developing breast and ovarian cancer in individuals who may be genetically susceptible to these diseases. Psychosocial issues associated with genetic testing are also discussed.

Genetics of Breast and Ovarian Cancer


General Information

Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.

Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.

Among women, breast cancer is the most commonly diagnosed cancer after nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after lung cancer. In 2014, an estimated 235,030 new cases will be diagnosed, and 40,430 deaths from breast cancer will occur. The incidence of breast cancer, particularly for estrogen receptor–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Women’s Health Initiative (WHI). An estimated 21,980 new cases of ovarian cancer are expected in 2014, with an estimated 14,270 deaths. Ovarian cancer is the fifth most deadly cancer in women. (Refer to the PDQ summaries on Breast Cancer Treatment and Ovarian Epithelial Cancer Treatment for more information about breast cancer and ovarian cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the increased incidence of these cancers among women with a family history (see the Family History as a Risk Factor for Breast Cancer and the Family History as a Risk Factor for Ovarian Cancer sections below), and by the observation of some families in which multiple family members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families ( linkage analysis) have subsequently proven the existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the identification of several highly penetrant genes as the cause of inherited cancer risk in many families. (Refer to the PDQ summary Cancer Genetics Overview for more information about linkage analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other genetic factors contribute to the etiology of some of these cancers.

Family History as a Risk Factor for Breast Cancer

In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer. The risk conferred by a family history of breast cancer has been assessed in case-control and cohort studies, using volunteer and population-based samples, with generally consistent results. In a pooled analysis of 38 studies, the relative risk (RR) of breast cancer conferred by an FDR with breast cancer was 2.1 (95% confidence interval [CI], 2.0–2.2). Risk increases with the number of affected relatives, age at diagnosis, and the number of affected male relatives. (Refer to the Penetrance of mutations section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 mutations who themselves test negative for the family mutation.)

Family History as a Risk Factor for Ovarian Cancer

Although reproductive, demographic, and lifestyle factors affect risk of ovarian cancer, the single greatest ovarian cancer risk factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.

Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition

Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

  • Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
  • Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition can still pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and of Cowden syndrome due to PTEN mutations. Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with Lynch syndrome, basal cell nevus (Gorlin) syndrome ( OMIM), and multiple endocrine neoplasia type 1 (OMIM). Germline mutations in the genes responsible for those syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary breast and ovarian cancer predisposition include the following:

  • Multiple cancers within a family.
  • Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).
  • Two or more primary cancers in a single individual. These could be multiple primary cancers of the same type (e.g., bilateral breast cancer) or primary cancer of different types (e.g., breast cancer and ovarian cancer in the same individual).
  • Cases of male breast cancer.

Figure 1 and Figure 2 depict some of the classic inheritance features of a deleterious BRCA1 and BRCA2 mutation, respectively. (Refer to the Standard Pedigree Nomenclature figure in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for definitions of the standard symbols used in these pedigrees.)

Pedigree showing some of the classic features of a family with a deleterious BRCA1 mutation across three generations, including transmission occurring through maternal and paternal lineages. The unaffected female proband is shown as having an affected mother (breast cancer diagnosed at age 42 y), female cousin (breast cancer diagnosed at age 38 y), maternal aunt (ovarian cancer diagnosed at age 53 y), and maternal grandmother (ovarian cancer diagnosed at age 49 y).
Figure 1. pedigree. This pedigree shows some of the classic features of a family with a deleterious mutation across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

Pedigree showing some of the classic features of a family with a deleterious BRCA2 mutation across three generations, including transmission occuring through maternal and paternal lineages. The unaffected female proband is shown as having an affected brother (breast cancer diagnosed at age 52 y), mother (breast cancer diagnosed at age 45 y and pancreatic cancer diagnosed at age 55 y), maternal aunt (ovarian cancer diagnosed at age 58 y), and maternal grandfather (prostate cancer diagnosed at age 55 y).
Figure 2. pedigree. This pedigree shows some of the classic features of a family with a deleterious mutation across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages, as depicted in the figure.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be estrogen receptor (ER)-negative, progesterone receptor–negative, and HER2/neu receptor-negative and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary for more information.)

Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk

When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.

Other Risk Factors for Breast Cancer

Other risk factors for breast cancer include age, reproductive and menstrual history, hormone therapy, radiation exposure, mammographic breast density, alcohol intake, physical activity, anthropometric variables, and a history of benign breast disease. (Refer to the PDQ summary on Breast Cancer Prevention for more information.) These factors, including their role in the etiology of breast cancer among BRCA1/BRCA2 mutation carriers, are considered in more detail in other reviews. Brief summaries are given below, highlighting, where possible, the effect of these risk factors in women who are genetically susceptible to breast cancer. (Refer to the Clinical management of BRCA mutation carriers section of this summary for more information about their effects in BRCA1/BRCA2 mutation carriers.)

Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years. In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

In general, breast cancer risk increases with early menarche and late menopause and is reduced by early first full-term pregnancy. In BRCA1 and BRCA2 mutation carriers, results have been conflicting and may be gene dependent. No consistent significant associations have been observed. Evidence suggests that reproductive history may be differentially associated with breast cancer subtype (i.e., triple-negative vs. ER-positive breast cancers). In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.

Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.

OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers. However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04). (Refer to the Reproductive factors section in the Clinical management of BRCA mutation carriers section of this summary for more information.)

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received therapeutic radiation treatments to the chest and upper body document increased breast cancer risk as a result of radiation exposure. The significance of this risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to radiation could be a cause of cancer susceptibility in carriers of BRCA1 or BRCA2 mutations, and in association with germline ATM and TP53 mutations.

The possibility that genetic susceptibility to breast cancer occurs via a mechanism of radiation sensitivity raises questions about radiation exposure. It is possible that diagnostic radiation exposure, including mammography, poses more risk in genetically susceptible women than in women of average risk. Therapeutic radiation could also pose carcinogenic risk. A cohort study of BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of mutation carriers. Conversely, radiation sensitivity could make tumors in women with genetic susceptibility to breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results. A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years. (Refer to the Mammography section in the High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes section of this summary for more information about radiation.)

The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population. Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.

Weight gain and being overweight are commonly recognized risk factors for breast cancer. In general, overweight women are most commonly observed to be at increased risk of postmenopausal breast cancer and at reduced risk of premenopausal breast cancer. Sedentary lifestyle may also be a risk factor. These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.

Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer). There may also be an association between BBD and family history of breast cancer.

An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram, and breast density is likely to have a genetic component in its etiology.

Other risk factors, including those that are only weakly associated with breast cancer and those that have been inconsistently associated with the disease in epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. For example, some studies have suggested that certain N-acetyl transferase alleles may influence female smokers’ risk of developing breast cancer. One study found a reduced risk of breast cancer among BRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.

Other Risk Factors for Ovarian Cancer

Factors that increase risk of ovarian cancer include increasing age and nulliparity, while those that decrease risk include surgical history and use of OCs. (Refer to the PDQ summary on Prevention of Ovarian Cancer for more information.) Relatively few studies have addressed the effect of these risk factors in women who are genetically susceptible to ovarian cancer. (Refer to the Reproductive factors section of this summary for more information.)

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers. Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid. Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk, including in BRCA1/BRCA2 mutation carriers. Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer. (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)

Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population. A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers. A meta-analysis of 18 studies including 13,627 BRCA mutation carriers reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use. (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)

Models for Prediction of Breast Cancer Risk

Models to predict an individual’s lifetime risk of developing breast cancer are available. In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about these models.) Not all models can be appropriately applied for all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models. Table 1 summarizes the salient aspects of two of the common risk assessment models and is designed to aid in choosing the model that best applies to a particular individual.

The Claus model and the Gail model are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models, which include more detailed family history information, are also in use and are discussed below.

The Gail and the Claus models will significantly underestimate breast cancer risk in women from families with hereditary breast cancer susceptibility syndromes. Generally, the Claus or the Gail models should not be the sole model used for families with one or more of the following characteristics:

  • Three individuals with breast or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).
  • A woman who has both breast and ovarian cancer.
  • Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model is the basis for the Breast Cancer Risk Assessment Tool, a computer program that is available from the National Cancer Institute by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography; however, reliability varies based on the cohort studied. Risk can be overestimated in:

  • Women who do not adhere to screening recommendations.
  • Women in the highest risk strata.

Risk could be underestimated in the lowest risk strata. Earlier studies suggested risk was overestimated in younger women and underestimated in older women. More recent studies using the modified Gail model (which is currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations. Recently, modifications have been made to the Breast Cancer Risk Assessment Tool incorporating data from the Women’s Contraceptive and Reproductive Experiences study. This study of more than 1,600 African American women with invasive breast cancer and more than 1,600 controls was used to develop a breast cancer risk assessment model with improved race-specific calibration. Additional information for seven common low-penetrance breast cancer susceptibility alleles has not been shown to improve model performance significantly.

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model in predicting breast cancer risk. The two models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of both the Gail and Claus models risk estimates may be useful in the counseling setting.

The Tyrer-Cuzick model incorporates both genetic and nongenetic factors. A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low-penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause, HRT use, and first live birth. Both genetic and nongenetic f actors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model examines family history to estimate breast cancer risk and also incorporates both BRCA1/BRCA2 and non-BRCA1/BRCA2 genetic risk factors.

Other risk assessment models incorporating breast density have been developed but are not ready for clinical use. In the future, additional models may be developed or refined to include such factors as breast density and other biomarkers.

High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes


Epidemiologic studies have clearly established the role of family history as an important risk factor for both breast and ovarian cancer. After gender and age, a positive family history is the strongest known predictive risk factor for breast cancer. However, it has long been recognized that in some families, there is hereditary breast cancer, which is characterized by an early age of onset, bilaterality, and the presence of breast cancer in multiple generations in an apparent autosomal dominant pattern of transmission (through either the maternal or paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland. It is now known that some of these “cancer families” can be explained by specific mutations in single cancer susceptibility genes. The isolation of several of these genes, which when mutated are associated with a significantly increased risk of breast/ovarian cancer, makes it possible to identify individuals at risk. Although such cancer susceptibility genes are very important, highly penetrant germline mutations are estimated to account for only 5% to 10% of breast cancers overall.

A 1988 study reported the first quantitative evidence that breast cancer segregated as an autosomal dominant trait in some families. The search for genes associated with hereditary susceptibility to breast cancer has been facilitated by studies of large kindreds with multiple affected individuals and has led to the identification of several susceptibility genes, including BRCA1, BRCA2, TP53, PTEN/MMAC1, and STK11. Other genes, such as the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, have been associated with an increased risk of ovarian cancer, but have not been consistently associated with breast cancer.

In 1990, a susceptibility gene for breast cancer was mapped by genetic linkage to the long arm of chromosome 17, in the interval 17q12-21. The linkage between breast cancer and genetic markers on chromosome 17q was soon confirmed by others, and evidence for the coincident transmission of both breast and ovarian cancer susceptibility in linked families was observed. The BRCA1 gene ( OMIM) was subsequently identified by positional cloning methods and has been found to contain 24 exons that encode a protein of 1,863 amino acids. Germline mutations in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of mutations section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with mutations in BRCA1; however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with mutations in BRCA2.

A second breast cancer susceptibility gene, BRCA2, was localized to the long arm of chromosome 13 through linkage studies of 15 families with multiple cases of breast cancer that were not linked to BRCA1. Mutations in BRCA2 ( OMIM) are associated with multiple cases of breast cancer in families, and are also associated with male breast cancer, ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. (Refer to the Penetrance of mutations section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids. While not homologous genes, both BRCA1 and BRCA2 have an unusually large exon 11 and translational start sites in exon 2. Like BRCA1, BRCA2 appears to behave like a tumor suppressor gene. In tumors associated with both BRCA1 and BRCA2 mutations, there is often loss of the wild-type (nonmutated) allele.

Mutations in BRCA1 and BRCA2 appear to be responsible for disease in 45% of families with multiple cases of breast cancer only and in up to 90% of families with both breast and ovarian cancer.

Most BRCA1 and BRCA2 mutations are predicted to produce a truncated protein product, and thus loss of protein function, although some missense mutations cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 mutation on one copy of chromosome 17 or 13 also carry a normal allele on the other paired chromosome. In most breast and ovarian cancers that have been studied from mutation carriers, deletion of the normal allele results in loss of all function, leading to the classification of BRCA1 and BRCA2 as tumor suppressor genes. In addition to, and as part of, their roles as tumor suppressor genes, BRCA1 and BRCA2 are involved in myriad functions within cells, including homologous DNA repair, genomic stability, transcriptional regulation, protein ubiquitination, chromatin remodeling, and cell cycle control.

Nearly 2,000 distinct mutations and sequence variations in BRCA1 and BRCA2 have already been described. Approximately one in 400 to 800 individuals in the general population may carry a pathogenic germline mutation in BRCA1 or BRCA2. The mutations that have been associated with increased risk of cancer result in missing or nonfunctional proteins, supporting the hypothesis that BRCA1 and BRCA2 are tumor suppressor genes. While a small number of these mutations have been found repeatedly in unrelated families, most have not been reported in more than a few families.

Mutation-screening methods vary in their sensitivity. Methods widely used in research laboratories, such as single-stranded conformational polymorphism analysis and conformation-sensitive gel electrophoresis, miss nearly a third of the mutations that are detected by DNA sequencing. In addition, large genomic alterations such as translocations, inversions, or large deletions or insertions are missed by most of the techniques, including direct DNA sequencing, but testing for these is commercially available. Such rearrangements are believed to be responsible for 12% to 18% of BRCA1 inactivating mutations but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish descent.

Statistics regarding the percentage of individuals found to be BRCA mutation carriers among samples of women and men with a variety of personal cancer histories regardless of family history are provided below. These data can help determine who might best benefit from a referral for cancer genetic counseling and consideration of genetic testing but cannot replace a personalized risk assessment, which might indicate a higher or lower mutation likelihood based on additional personal and family history characteristics.

In some cases, the same mutation has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a mutation identified in a contemporary population can be traced to a small group of founders isolated by geographic, cultural, or other factors. Most notably, two specific BRCA1 mutations (185delAG and 5382insC) and a BRCA2 mutation (6174delT) have been reported to be common in Ashkenazi Jews. However, other founder mutations have been identified in African Americans and Hispanics. The presence of these founder mutations has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, it is estimated that up to 15% of BRCA1 and BRCA2 mutations that occur among Ashkenazim are nonfounder mutations.

Among the general population, the likelihood of having any BRCA mutation is as follows:

  • General population (excluding Ashkenazim): about 1 in 400 (~0.25%).
  • Women with breast cancer (any age): 1 in 50 (2%).
  • Women with breast cancer (younger than 40 years): 1 in 10 (10%).
  • Men with breast cancer (any age): 1 in 20 (5%).
  • Women with ovarian cancer (any age): 1 in 8 to 1 in 10 (10%–15%).

Among Ashkenazi Jewish individuals, the likelihood of having any BRCA mutation is as follows:

  • General Ashkenazi Jewish population: 1 in 40 (2.5%).
  • Women with breast cancer (any age): 1 in 10 (10%).
  • Women with breast cancer (younger than 40 years): 1 in 3 (30%–35%).
  • Men with breast cancer (any age): 1 in 5 (19%).
  • Women with ovarian cancer or primary peritoneal cancer (all ages): 1 in 3 (36%–41%).

Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 and BRCA2 mutations in various ethnic groups. The prevalence of BRCA1 mutations in breast cancer patients by ethnic group was 3.5% in Hispanics, 1.3% to 1.4% in African Americans, 0.5% in Asian Americans, 2.2% to 2.9% in non-Ashkenazi Caucasians, and 8.3% to 10.2% in Ashkenazi Jewish individuals. The prevalence of BRCA2 mutations by ethnic group was 2.6% in African Americans and 2.1% in Caucasians.

A study of Hispanic patients with a personal or family history of breast cancer and/or ovarian cancer, who were enrolled through multiple clinics in the southwestern United States, examined the prevalence of BRCA1 and BRCA2 mutations. Deleterious BRCA mutations were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2); 21 of the 189 (11%) deleterious BRCA mutations identified were large rearrangements, of which 13 (62%) were BRCA1 ex9-12 deletions. In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 ex9-12 deletion was found in three patients, suggesting that this mutation may be a Mexican founder mutation and may represent 10% to 12% of all BRCA1 mutations in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent mutations, which accounted for 53% of all mutations observed in this cohort, suggesting the existence of additional founder mutations in this population.

A retrospective review of 29 Ashkenazi Jewish patients with primary fallopian tube tumors identified germline BRCA mutations in 17%. Another study of 108 women with fallopian tube cancer identified mutations in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall). Estimates of the frequency of fallopian tube cancer in BRCA mutation carriers are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.

Several studies have assessed the frequency of BRCA1 or BRCA2 mutations in women with breast or ovarian cancer. Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 mutation include the following:

  • Breast cancer diagnosed at an early age. (Some studies use age 40 years, while others use age 50 years as a cutoff.)
  • Ovarian cancer.
  • Bilateral breast cancer.
  • A history of both breast and ovarian cancer.
  • Breast cancer diagnosed in a male at any age.
  • Triple-negative breast cancer diagnosed in women younger than 50 years.
  • Ashkenazi Jewish background.

Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 mutation include the following:

  • Multiple cases of breast cancer.
  • Both breast and ovarian cancer.
  • One or more breast cancers in male family members.
  • Ashkenazi Jewish background.

Genetic testing for BRCA1 and BRCA2 mutations has been available to the public since 1996. As more individuals have undergone testing, risk assessment models have improved. This, in turn, gives providers better data to estimate an individual patient’s risk of carrying a mutation, but risk assessment continues to be an art. There are factors that might limit the ability to provide an accurate risk assessment (i.e., small family size, paucity of women, or ethnicity) including the specific circumstances of the individual patient (such as history of disease or prophylactic surgeries).

The proportion of individuals carrying a mutation who will manifest the disease is referred to as penetrance. In general, common genetic variants that are associated with cancer susceptibility have a lower penetrance than rare genetic variants. This is depicted in Figure 3. For adult-onset diseases, penetrance is usually described by the individual carrier's age and sex. For example, the penetrance for breast cancer in female BRCA1/BRCA2 mutation carriers is often quoted by age 50 years and by age 70 years. Of the numerous methods for estimating penetrance, none are without potential biases, and determining an individual mutation carrier's risk of cancer involves some level of imprecision.

Numerous studies have estimated breast and ovarian cancer penetrance in BRCA1 and BRCA2 mutation carriers. Risk of both breast and ovarian cancer is consistently estimated to be higher in BRCA1 than in BRCA2 mutation carriers. Results from two large meta-analyses are shown in Table 3. One study analyzed pooled pedigree data from 22 studies involving 289 BRCA1 and 221 BRCA2 mutation–positive individuals. Index cases from these studies had female breast cancer, male breast cancer, or ovarian cancer but were unselected for family history. A subsequent study combined penetrance estimates from the previous study and nine others that included an additional 734 BRCA1 and 400 BRCA2 mutation–positive families. The estimated cumulative risks of breast cancer by age 70 years in these two meta-analyses were 55% to 65% for BRCA1 and 45% to 47% for BRCA2 mutation carriers. Ovarian cancer risks were 39% for BRCA1 and 11% to 17% for BRCA2 mutation carriers.

While the cumulative risks of cancer by age 70 years are higher for BRCA1 than BRCA2 mutation carriers, the relative risks (RR) of breast cancer decline with age more in BRCA1 mutation carriers. Studies of penetrance for carriers of specific individual mutations are not usually large enough to provide stable estimates, but numerous studies of the Ashkenazi founder mutations have been conducted. One group of researchers analyzed the subset of families with one of the Ashkenazi founder mutations from their larger meta-analyses and found that the estimated penetrance for the individual mutations was very similar to the corresponding estimates among all mutation carriers.

One study provided prospective 10-year risks of developing cancer among asymptomatic carriers at various ages. Nonetheless, making precise penetrance estimates in an individual carrier is difficult.

Risk-reducing salpingo-oophorectomy and/or use of oral contraceptives have been shown to alter risk. (Refer to the Risk-reducing salpingo-oophorectomy section and the Oral contraceptives section of this summary for more information.) Other environmental factors being studied include reproductive and hormonal factors. Genetic modifiers of penetrance of breast cancer and ovarian cancer are increasingly under study but are not clinically useful at this time. While the average breast cancer and ovarian cancer penetrances may not be as high as initially estimated, they are substantial, both in relative and absolute terms, particularly in women born after 1940. A higher risk before age 50 years has been consistently seen in more recent birth cohorts, and additional studies will be required to further characterize potential modifying factors to arrive at more precise individual risk projections. Precise penetrance estimates for less common cancers, such as pancreatic cancer, are lacking.

Given that germline mutations in BRCA1 or BRCA2 lead to a very high probability of developing breast and/or ovarian cancer, it was a natural assumption that these genes would also be involved in the development of the more common nonhereditary forms of the disease. Although somatic mutations in BRCA1 and BRCA2 are not common in sporadic breast and ovarian cancer tumors, there is increasing evidence that downregulation of BRCA1 protein expression may play a role in these tumor types. Compared with normal breast epithelium, many breast cancers have low levels of the BRCA1 mRNA, which may result from hypermethylation of the gene promoter. Similar findings have not been reported for BRCA2 mutations, although the BRCA2 locus on chromosome 13q is the target of frequent loss of heterozygosity (LOH) in breast cancer. Approximately 10% to 15% of sporadic breast cancers appear to have BRCA1 promoter hypermethylation, and even more have downregulation of BRCA1 by other mechanisms. Basal-type breast cancers (ER-negative, PR-negative, HER2-negative, and cytokeratin 5/6–positive) more commonly have BRCA1 dysregulation than other tumor types. BRCA1-related tumor characteristics have also been associated with constitutional methylation of the BRCA1 promoter. In a study of 255 breast cancers diagnosed before age 40 years in women without germline BRCA1 mutations, methylation of BRCA1 in peripheral blood was observed in 31% of women whose tumors had multiple BRCA1-associated pathological characteristics (e.g., high mitotic index and growth pattern including multinucleated cells) compared with less than 4% methylation in controls. (Refer to the BRCA1 pathology section for more information.) Loss of BRCA1 or BRCA2 protein expression is more common in ovarian cancer than in breast cancer, and downregulation of BRCA1 is associated with enhanced sensitivity to cisplatin and improved survival in this disease. Targeted therapies are being developed for tumors with loss of BRCA1 or BRCA2 protein expression.

Some genotype-phenotype correlations have been identified in both BRCA1 and BRCA2 mutation families. None of the studies have had sufficient numbers of mutation-positive individuals to make definitive conclusions, and the findings are probably not sufficiently established to use in individual risk assessment and management. In 25 families with BRCA2 mutations, an ovarian cancer cluster region was identified in exon 11 bordered by nucleotides 3,035 and 6,629. This is the region of the gene containing the BRCA1 C-terminal repeat, which has been shown to specifically interact with RAD51. A study of 164 families with BRCA2 mutations collected by the Breast Cancer Linkage Consortium confirmed the initial finding. Mutations within the ovarian cancer cluster region were associated with an increased risk of ovarian cancer and a decreased risk of breast cancer in comparison to families with mutations on either side of this region. In addition, a study of 356 families with protein-truncating BRCA1 mutations collected by the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with mutations in the central region (nucleotides 2,401–4,190) compared with surrounding regions. Ovarian cancer risk was significantly reduced with mutations 3’ to nucleotide 4,191. These observations have generally been confirmed in subsequent studies. Studies in Ashkenazim, in whom substantial numbers of families with the same mutation can be studied, have also found higher rates of ovarian cancer in carriers of the BRCA1:185delAG mutation, in the 5' end of BRCA1, compared with carriers of the BRCA1:5382insC mutation in the 3' end of the gene. The risk of breast cancer, particularly bilateral breast cancer, and the occurrence of both breast and ovarian cancer in the same individual, however, appear to be higher in BRCA1:5382insC mutation carriers compared with carriers of BRCA1:185delAG and BRCA2:6174delT mutations. Ovarian cancer risk is considerably higher in BRCA1 mutation carriers, and it is uncommon before age 45 years in BRCA2:6174delT mutation carriers.

High-grade serous carcinomas are most likely to be attributable to BRCA mutations, with rates estimated to be between 74% and 80% among carriers, compared with up to 67% in the general population. In contrast, BRCA mutations are less likely to be seen in patients with mucinous or borderline cancers. Fallopian tube cancer and papillary serous carcinoma of the peritoneum are also part of the spectrum of BRCA-associated disease. Patients with invasive epithelial ovarian cancers have the highest risk of carrying a BRCA mutation, compared with patients with other histologies. Serous carcinoma was also found to be the predominant histologic subtype of intraperitoneal carcinoma among BRCA1/BRCA2 carriers in a Dutch case-control study. In contrast to high-grade serous ovarian cancer, low-grade serous ovarian cancer is not likely to be part of the spectrum of BRCA1- or BRCA2-related ovarian cancer. Both primary ovarian carcinomas and primary peritoneal carcinomas have a higher incidence of somatic TP53 mutations and exhibit relatively aggressive features, including higher grade and p53 overexpression. The finding of differential expression of genes in BRCA1, BRCA2, and sporadic ovarian cancer, using DNA microarray technology, suggests distinct molecular pathways of carcinogenesis that may ultimately distinguish them histologically. Furthermore, there have been data to suggest that BRCA-related ovarian cancers that relapse frequently metastasize to viscera, while relapsed sporadic ovarian cancers commonly remain confined to the peritoneum.

Histopathologic examinations of fallopian tubes removed prophylactically from women with a hereditary predisposition to ovarian cancer show dysplastic and hyperplastic lesions that are accompanied by changes in cell-cycle and apoptosis-related proteins, suggesting a premalignant phenotype. Occult carcinomas have been reported in 2% to 11% of the adnexa removed at the time of risk-reducing surgery from BRCA mutation carriers. The majority of these occult carcinomas are seen within the fallopian tube, which has led to the hypothesis that many BRCA-associated ovarian cancers may actually have originated in the fallopian tube. Specifically, the distal segment of the fallopian tube (fimbriae) has been implicated as a common origin for the high-grade serous cancers seen in BRCA mutation carriers based on its close proximity to the ovarian surface and peritoneal cavity and its large surface area.

Increasing data are available on the outcomes of interventions to reduce risk in people with a genetic susceptibility to breast cancer or ovarian cancer. As outlined in other sections of this summary, uncertainty is often considerable regarding the level of cancer risk associated with a positive family history or genetic test. In this setting, personal preferences are likely to be an important factor in patients’ decisions about risk reduction strategies.

Other High-Penetrance Syndromes Associated with Breast and/or Ovarian Cancer

Lynch syndrome (LS) is characterized by autosomal dominant inheritance of susceptibility to predominantly right-sided colon cancer, endometrial cancer, ovarian cancer, and other extracolonic cancers (including cancer of the renal pelvis, ureter, small bowel, and pancreas), multiple primary cancers, and a young age of onset of cancer. The condition is caused by germline mutations in the MMR genes, which are involved in repair of DNA mismatch mutations. The MLH1 and MSH2 genes are the most common susceptibility genes for LS, accounting for 80% to 90% of observed mutations, followed by MSH6 and PMS2. (Refer to the Lynch syndrome (LS) section in the PDQ summary on Genetics of Colorectal Cancer for more information about this syndrome.)

The lifetime risk of ovarian carcinoma in females with LS is estimated to be as high as 12%, and the reported RR of ovarian cancer has ranged from 3.6 to 13, based on families ascertained from high-risk clinics with known or suspected LS. Characteristics of LS-associated ovarian cancers may include overrepresentation of the International Federation of Gynecology and Obstetrics stages 1 and 2 at diagnosis (reported as 81.5%), underrepresentation of serous subtypes (reported as 22.9%), and a better 10-year survival (reported as 80.6%) than reported both in population-based series and in BRCA mutation carriers.

Breast cancer is also a component of the rare Li-Fraumeni syndrome (LFS) ( OMIM), in which germline mutations of the TP53 gene (OMIM) on chromosome 17p have been documented. This syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Tumors in LFS families tend to occur in childhood and early adulthood, and often present as multiple primaries in the same individual. Evidence supports a genotype-phenotype correlation, with an association of the location of the mutation, the kind of cancer that develops, and the age of onset. Brain and adrenal gland tumors were associated with specific sites of missense mutations. Age at onset of breast cancer was 34.6 years in families with a TP53 mutation compared with 42.5 years in those families without a mutation. A germline mutation in the TP53 gene has been identified in more than 50% of families exhibiting this syndrome, and inheritance is autosomal dominant, with a penetrance of at least 50% by age 50 years.

Germline TP53 mutations were identified in 17% (n = 91) of 525 samples submitted to City of Hope laboratories for clinical TP53 testing. All families with a TP53 mutation had at least one family member with a sarcoma, breast cancer, brain cancer, or adrenocortical cancer (core cancers). In addition, all eight individuals with a choroid plexus tumor had a TP53 mutation, as did 14 of the 21 individuals with childhood adrenocortical cancer. In women aged 30 to 49 years who had breast cancer but no family history of other core cancers, no TP53 mutations were found. TP53 mutations are uncommon in women with breast cancer before age 30 years with no other indications for TP53 screening (e.g., a family history of sarcoma). In three studies, the numbers of women with


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