Executive Summary
This executive summary reviews the topics covered in this PDQ summary on the genetics of breast and gynecologic cancers, with hyperlinks to detailed sections below that describe the evidence on each topic.
Breast and ovarian cancer are present in several autosomal dominant cancer syndromes, although they are most strongly associated with highly penetrant germline pathogenic variants in BRCA1 and BRCA2. Other genes, such as PALB2, TP53 (associated with Li-Fraumeni syndrome), PTEN (associated with Cowden syndrome), CDH1 (associated with diffuse gastric and lobular breast cancer syndrome), and STK11 (associated with Peutz-Jeghers syndrome), confer a risk to either or both of these cancers with relatively high penetrance.
Inherited endometrial cancer is most commonly associated with LS, a condition caused by inherited pathogenic variants in the highly penetrant mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. Colorectal cancer (and, to a lesser extent, ovarian cancer and stomach cancer) is also associated with LS.
Additional genes, such as CHEK2, BRIP1, RAD51, and ATM, are associated with breast and/or gynecologic cancers with moderate penetrance. Genome-wide searches are showing promise in identifying common, low-penetrance susceptibility alleles for many complex diseases, including breast and gynecologic cancers, but the clinical utility of these findings remains uncertain.
Breast cancer screening strategies, including breast magnetic resonance imaging and mammography, are commonly performed in carriers of BRCA pathogenic variants and in individuals at increased risk of breast cancer. Initiation of screening is generally recommended at earlier ages and at more frequent intervals in individuals with an increased risk due to genetics and family history than in the general population. There is evidence to demonstrate that these strategies have utility in early detection of cancer. In contrast, there is currently no evidence to demonstrate that gynecologic cancer screening using cancer antigen 125 testing and transvaginal ultrasound leads to early detection of cancer.
Risk-reducing surgeries, including risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), have been shown to significantly reduce the risk of developing breast and/or ovarian cancer and improve overall survival in carriers of BRCA1 and BRCA2 pathogenic variants. Chemoprevention strategies, including the use of tamoxifen and oral contraceptives, have also been examined in this population. Tamoxifen use has been shown to reduce the risk of contralateral breast cancer among carriers of BRCA1 and BRCA2 pathogenic variants after treatment for breast cancer, but there are limited data in the primary cancer prevention setting to suggest that it reduces the risk of breast cancer among healthy female carriers of BRCA2 pathogenic variants. The use of oral contraceptives has been associated with a protective effect on the risk of developing ovarian cancer, including in carriers of BRCA1 and BRCA2 pathogenic variants, with no association of increased risk of breast cancer when using formulations developed after 1975.
Psychosocial factors influence decisions about genetic testing for inherited cancer risk and risk-management strategies. Uptake of genetic testing varies widely across studies. Psychological factors that have been associated with testing uptake include cancer-specific distress and perceived risk of developing breast or ovarian cancer. Studies have shown low levels of distress after genetic testing for both carriers and noncarriers, particularly in the longer term. Uptake of RRM and RRSO also varies across studies, and may be influenced by factors such as cancer history, age, family history, recommendations of the health care provider, and pretreatment genetic education and counseling. Patients' communication with their family members about an inherited risk of breast and gynecologic cancer is complex; gender, age, and the degree of relatedness are some elements that affect disclosure of this information. Research is ongoing to better understand and address psychosocial and behavioral issues in high-risk families.
[Note: 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.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term variant rather than the term mutation to describe a genetic difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
[Note: 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 2016, an estimated 249,260 new cases will be diagnosed, and 40,890 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptorpositive 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 Womens Health Initiative (WHI).[2] An estimated 22,280 new cases of ovarian cancer are expected in 2016, with an estimated 14,240 deaths. Ovarian cancer is the fifth most deadly cancer in women.[1] An estimated 60,050 new cases of endometrial cancer are expected in 2016, with an estimated 10,470 deaths.[1] (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial 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 (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), 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.) Pathogenic variants 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.
Refer to the PDQ summary on Breast Cancer Prevention for information about risk factors for breast cancer in the general population.
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.[3-6] 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.[7] 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], 2.02.2).[7] Risk increases with the number of affected relatives, age at diagnosis, the occurrence of bilateral or multiple ipsilateral breast cancers in a family member, and the number of affected male relatives.[4,5,7-9] A large population-based study from the Swedish Family Cancer Database confirmed the finding of a significantly increased risk of breast cancer in women who had a mother or a sister with breast cancer. The hazard ratio (HR) for women with a single breast cancer in the family was 1.8 (95% CI, 1.81.9) and was 2.7 (95% CI, 2.62.9) for women with a family history of multiple breast cancers. For women who had multiple breast cancers in the family, with one occurring before age 40 years, the HR was 3.8 (95% CI, 3.14.8). However, the study also found a significant increase in breast cancer risk if the relative was aged 60 years or older, suggesting that breast cancer at any age in the family carries some increase in risk.[9] (Refer to the Penetrance of BRCA pathogenic variants section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 pathogenic variants who themselves test negative for the family pathogenic variant.)
Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[10] 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. There may be an increased risk of breast cancer in carriers of BRCA1 and BRCA2 pathogenic variants with pregnancy at a younger age (before age 30 years), with a more significant effect seen for carriers of BRCA1 pathogenic variants.[11-13] Likewise, breast feeding can reduce breast cancer risk in carriers of BRCA1 (but not BRCA2) pathogenic variants.[14] Regarding the effect of pregnancy on breast cancer outcomes, neither diagnosis of breast cancer during pregnancy nor pregnancy after breast cancer seems to be associated with adverse survival outcomes in women who carry a BRCA1 or BRCA2 pathogenic variant.[15] Parity appears to be protective for carriers of BRCA1 and BRCA2 pathogenic variants, with an additional protective effect for live birth before age 40 years.[16]
Reproductive history can also affect the risk of ovarian cancer and endometrial cancer. (Refer to the Reproductive History sections in the Risk Factors for Ovarian Cancer and Risk Factors for Endometrial Cancer sections of this summary for more information.)
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.[17]
OCs are sometimes recommended for ovarian cancer prevention in carriers of BRCA1 and BRCA2 pathogenic variants. (Refer to the Oral Contraceptives section in the Risk Factors for Ovarian Cancer section of this summary for more information.) 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 carriers of BRCA1/BRCA2 pathogenic variants.[18] However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.062.04).[18] (Refer to the Reproductive factors section in the Clinical Management of Carriers of BRCA Pathogenic Variants section of this summary for more information.)
Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51 observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.211.49) for women who had used HRT for 5 or more years after menopause.[19] The WHI (NCT00000611), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[20,21] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.021.5, P < . 001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Womens Study in the United Kingdom.[22] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR, 0.77; 95% CI, 0.591.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[23]
The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[24-28,19] The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history.[28] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 pathogenic variants.[21] Short-term use of hormones for treatment of menopausal symptoms appears to confer little or no breast cancer risk.[19,29] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 pathogenic variants has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[30] (Refer to the Hormone replacement therapy in carriers of BRCA1/BRCA2 pathogenic variants section of this summary for more information.)
Hormone use can also affect the risk of developing endometrial cancer. (Refer to the Hormones section in the Risk Factors for Endometrial Cancer 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 pathogenic variants,[31-34] and in association with germline ATM and TP53 variants.[35,36]
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 carriers of BRCA1 and BRCA2 pathogenic variants treated with breast-conserving therapy, however, showed no evidence of increased radiation sensitivity or sequelae in the breast, lung, or bone marrow of carriers.[37] 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 carriers of BRCA1 and BRCA2 pathogenic variants have had conflicting results.[38-43] 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.[42] Subsequently, no significant association was observed between prior mammography exposure and breast cancer risk in a prospective study of 1,844 BRCA1 carriers and 502 BRCA2 carriers without a breast cancer diagnosis at time of study entry; average follow-up time was 5.3 years.[43] (Refer to the Mammography section in the Clinical Management of Carriers of BRCA Pathogenic Variants 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.[44,45] Prior studies of carriers of BRCA1/BRCA2 pathogenic variants have found no increased risk associated with alcohol consumption.[46,47]
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.[48] These factors have not been systematically evaluated in women with a positive family history of breast cancer or in carriers of cancer-predisposing pathogenic variants, but one study suggested a reduced risk of cancer associated with exercise among carriers of BRCA1 and BRCA2 pathogenic variants.[49]
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).[50] There may also be an association between BBD and family history of breast cancer.[51]
An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[50,52,53] and breast density is likely to have a genetic component in its etiology.[54-56]
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. One study [57] found a reduced risk of breast cancer among carriers of BRCA1/BRCA2 pathogenic variants who smoked, but an expanded follow-up study failed to find an association.[58]
Refer to the PDQ summary on Ovarian, Fallopian Tube, and Primary Peritoneal Cancer Prevention for information about risk factors for ovarian cancer in the general population.
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.[59]
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.[60]
Nulliparity is consistently associated with an increased risk of ovarian cancer, including among carriers of BRCA/BRCA2 pathogenic variants, yet a meta-analysis could only identify risk-reduction in women with four or more live births.[13] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[61,62] Several studies have reported a risk reduction in ovarian cancer after OC pill use in carriers of BRCA1/BRCA2 pathogenic variants;[63-65] a risk reduction has also been shown after tubal ligation in BRCA1 carriers, with a statistically significant decreased risk of 22% to 80% after the procedure.[65,66] On the other hand, 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.[67-70]
Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[61,71,72] including in carriers of BRCA1/BRCA2 pathogenic variants.[73] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 pathogenic variants who chose risk-reducing salpingo-oophorectomy. In this same population, risk-reducing oophorectomy also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[74,75] (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.[61,76] A majority of, but not all, studies also support OCs being protective among carriers of BRCA1/BRCA2 pathogenic variants.[66,77-80] A meta-analysis of 18 studies including 13,627 carriers of BRCA pathogenic variants reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.330.75) associated with OC use.[18] (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)
Refer to the PDQ summary on Endometrial Cancer Prevention for information about risk factors for endometrial cancer in the general population.
Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a womans risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause,[81] with the main hereditary endometrial cancer syndrome being Lynch syndrome (LS), an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals.[82,83] (Refer to the LS section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years.[84] Women with LS tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.[85]
Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.[86,87]
Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome (PCOS), and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use.[88,89] Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer.[90] In contrast, oral contraceptives, the levonorgestrel-releasing intrauterine system, and combination estrogen-progesterone hormone replacement therapy all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.[91-94]
Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of cancer predisposition from generation to generation, through either the mothers or the fathers side of the family, with the following characteristics:
Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the syndromes associated with BRCA1 or BRCA2 pathogenic variants. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 pathogenic variants and of Cowden syndrome due to PTEN pathogenic variants.[95] 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 LS, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (OMIM).[95] LS is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).[96-102]
Germline pathogenic variants in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.
The family characteristics that suggest hereditary cancer predisposition include the following:
Figure 1 and Figure 2 depict some of the classic inheritance features of a BRCA1 and BRCA2 pathogenic variant, respectively. Figure 3 depicts a classic family with LS. (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.)
Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a BRCA1 pathogenic variant across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA1 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a BRCA2 pathogenic variant 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. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a BRCA2 pathogenic variant can be transmitted through maternal or paternal lineages, as depicted in the figure.
Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.
There are no pathognomonic features distinguishing breast and ovarian cancers occurring in carriers of BRCA1 or BRCA2 pathogenic variants from those occurring in noncarriers. Breast cancers occurring in carriers of BRCA1 pathogenic variants are more likely to be ER-negative, progesterone receptornegative, HER2/neu receptornegative (i.e., triple-negative breast cancers), 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.)
Some pathologic features distinguish carriers of LS-associated pathogenic variants from noncarriers. The hallmark feature of endometrial cancers occurring in LS is mismatch repair (MMR) defects, including the presence of microsatellite instability (MSI), and the absence of specific MMR proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.
The accuracy and completeness of family histories must be taken into account when they are used to assess risk. 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 does breast or ovarian cancer on the maternal side, so information may be more difficult to obtain. When self-reported information is compared 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%.[103,104] Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
Models to predict an individuals lifetime risk of developing breast and/or gynecologic cancer are available.[105-108] In addition, models exist to predict an individuals likelihood of having a pathogenic variant in BRCA1, BRCA2, or one of the MMR genes associated with LS. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 pathogenic variant section of this summary for more information about some of these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patients characteristics and family history are similar to those of 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.[106,109,110]
In general, breast cancer risk assessment models are designed for two types of populations: 1) women without a pathogenic variant or strong family history of breast or ovarian cancer; and 2) women at higher risk because of a personal or family history of breast cancer or ovarian cancer.[110] Models designed for women of the first type (e.g., the Gail model, which is the basis for the Breast Cancer Risk Assessment Tool [BCRAT]) [111], and the Colditz and Rosner model [112]) require only limited information about family history (e.g., number of first-degree relatives with breast cancer). Models designed for women at higher risk require more detailed information about personal and family cancer history of breast and ovarian cancers, including ages at onset of cancer and/or carrier status of specific breast cancer-susceptibility alleles. The genetic factors used by the latter models differ, with some assuming one risk locus (e.g., the Claus model [113]), others assuming two loci (e.g., the International Breast Cancer Intervention Study [IBIS] model [114] and the BRCAPRO model [115]), and still others assuming an additional polygenic component in addition to multiple loci (e.g., the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA] model [116-118]). The models also differ in whether they include information about nongenetic risk factors. Three models (Gail/BCRAT, Pfeiffer,[108] and IBIS) include nongenetic risk factors but differ in the risk factors they include (e.g., the Pfeiffer model includes alcohol consumption, whereas the Gail/BCRAT does not). These models have limited ability to discriminate between individuals who are affected and those who are unaffected with cancer; a model with high discrimination would be close to 1, and a model with little discrimination would be close to 0.5; the discrimination of the models currently ranges between 0.56 and 0.63).[119] The existing models generally are more accurate in prospective studies that have assessed how well they predict future cancers.[110,120-122]
In the United States, BRCAPRO, the Claus model,[113,123] and the Gail/BCRAT [111] are widely used in clinical counseling. Risk estimates derived from the models differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.
The Gail model is the basis for the BCRAT, a computer program available from the National Cancer Institute (NCI) 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/BCRAT 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 depending on the cohort studied.[124-129] Risk can be overestimated in the following populations:
The Gail/BCRAT model is valid for women aged 35 years and older. The model was primarily developed for white women.[128] Extensions of the Gail model for African American women have been subsequently developed to calibrate risk estimates using data from more than 1,600 African American women with invasive breast cancer and more than 1,600 controls.[130] Additionally, extensions of the Gail model have incorporated high-risk single nucleotide polymorphisms and pathogenic variants; however, no software exists to calculate risk in these extended models.[131,132] Other risk assessment models incorporating breast density have been developed but are not ready for clinical use.[133,134]
Generally, the Gail/BCRAT model should not be the sole model used for families with one or more of the following characteristics:
Commonly used models that incorporate family history include the IBIS, BOADICEA, and BRCAPRO models. The IBIS/Tyrer-Cuzick model incorporates both genetic and nongenetic factors.[114] A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 pathogenic variant or a hypothetical low-penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index (BMI); height; and age at menarche, first live birth, menopause, and HRT use. Both genetic and nongenetic factors are combined to develop a risk estimate. The BOADICEA model examines family history to estimate breast cancer risk and also incorporates both BRCA1/BRCA2 and non-BRCA1/BRCA2 genetic risk factors.[117] The most important difference between BOADICEA and the other models using information on BRCA1/BRCA2 is that BOADICEA assumes an additional polygenic component in addition to multiple loci,[116-118] which is more in line with what is known about the underlying genetics of breast cancer. However, the discrimination and calibration for these models differ significantly when compared in independent samples;[120] the IBIS and BOADICEA models are more comparable when estimating risk over a shorter fixed time horizon (e.g., 10 years),[120] than when estimating remaining lifetime risk. As all risk assessment models for cancers are typically validated over a shorter time horizon (e.g., 5 or 10 years), fixed time horizon estimates rather than remaining lifetime risk may be more accurate and useful measures to convey in a clinical setting.
In addition, readily available models that provide information about an individual womans risk in relation to the population-level risk depending on her risk factors may be useful in a clinical setting (e.g., Your Disease Risk). Although this tool was developed using information about average-risk women and does not calculate absolute risk estimates, it still may be useful when counseling women about prevention. Risk assessment models are being developed and validated in large cohorts to integrate genetic and nongenetic data, breast density, and other biomarkers.
Two risk predictions models have been developed for ovarian cancer.[107,108] The Rosner model [107] included age at menopause, age at menarche, oral contraception use, and tubal ligation; the concordance statistic was 0.60 (0.570.62). The Pfeiffer model [108] included oral contraceptive use, menopausal hormone therapy use, and family history of breast cancer or ovarian cancer, with a similar discriminatory power of 0.59 (0.560.62). Although both models were well calibrated, their modest discriminatory power limited their screening potential.
The Pfeiffer model has been used to predict endometrial cancer risk in the general population.[108] For endometrial cancer, the relative risk model included BMI, menopausal hormone therapy use, menopausal status, age at menopause, smoking status, and oral contraceptive pill use. The discriminatory power of the model was 0.68 (0.660.70); it overestimated observed endometrial cancers in most subgroups but underestimated disease in women with the highest BMI category, in premenopausal women, and in women taking menopausal hormone therapy for 10 years or more.
In contrast, MMRpredict, PREMM1,2,6, and MMRpro are three quantitative predictive models used to identify individuals who may potentially have LS.[135-137] MMRpredict incorporates only colorectal cancer patients but does include MSI and immunohistochemistry (IHC) tumor testing results. PREMM1,2,6 accounts for other LS-associated tumors but does not include tumor testing results. MMRpro incorporates tumor testing and germline testing results, but is more time intensive because it includes affected and unaffected individuals in the risk-quantification process. All three predictive models are comparable to the traditional Amsterdam and Bethesda criteria in identifying individuals with colorectal cancer who carry MMR gene pathogenic variants.[138] However, because these models were developed and validated in colorectal cancer patients, the discriminative abilities of these models to identify LS are lower among individuals with endometrial cancer than among those with colon cancer.[139] In fact, the sensitivity and specificity of MSI and IHC in identifying carriers of pathogenic variants are considerably higher than the prediction models and support the use of molecular tumor testing to screen for LS in women with endometrial cancer.
Table 1 summarizes salient aspects of breast and gynecologic cancer risk assessment models that are commonly used in the clinical setting. These models differ by the extent of family history included, whether nongenetic risk factors are included, and whether carrier status and polygenic risk are included (inputs to the models). The models also differ in the type of risk estimates that are generated (outputs of the models). These factors may be relevant in choosing the model that best applies to a particular individual.
The proportion of individuals carrying a pathogenic variant who will manifest a certain 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 4. For adult-onset diseases, penetrance is usually described by the individual carrier's age, sex, and organ site. For example, the penetrance for breast cancer in female carriers of BRCA1 pathogenic variants 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 carrier's risk of cancer involves some level of imprecision.
Figure 4. Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as pathogenic variants in the BRCA1/BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.
Throughout this summary, we discuss studies that report on relative and absolute risks. These are two important but different concepts. Relative risk (RR) refers to an estimate of risk relative to another group (e.g., risk of an outcome like breast cancer for women who are exposed to a risk factor RELATIVE to the risk of breast cancer for women who are unexposed to the same risk factor). RR measures that are greater than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is higher than the risk for those captured in the denominator (i.e., the unexposed). RR measures that are less than 1 mean that the risk for those captured in the numerator (i.e., the exposed) is lower than the risk for those captured in the denominator (i.e., the unexposed). Measures with similar relative interpretations include the odds ratio (OR), hazard ratio (HR), and risk ratio.
Absolute risk measures take into account the number of people who have a particular outcome, the number of people in a population who could have the outcome, and person-time (the period of time during which an individual was at risk of having the outcome), and reflect the absolute burden of an outcome in a population. Absolute measures include risks and rates and can be expressed over a specific time frame (e.g., 1 year, 5 years) or overall lifetime. Cumulative risk is a measure of risk that occurs over a defined time period. For example, overall lifetime risk is a type of cumulative risk that is usually calculated on the basis of a given life expectancy (e.g., 80 or 90 years). Cumulative risk can also be presented over other time frames (e.g., up to age 50 years).
Large relative risk measures do not mean that there will be large effects in the actual number of individuals at a population level because the disease outcome may be quite rare. For example, the relative risk for smoking is much higher for lung cancer than for heart disease, but the absolute difference between smokers and nonsmokers is greater for heart disease, the more-common outcome, than for lung cancer, the more-rare outcome.
Therefore, in evaluating the effect of exposures and biological markers on disease prevention across the continuum, it is important to recognize the differences between relative and absolute effects in weighing the overall impact of a given risk factor. For example, the magnitude is in the range of 30% (e.g., ORs or RRs of 1.3) for many breast cancer risk factors, which means that women with a risk factor (e.g., alcohol consumption, late age at first birth, oral contraceptive use, postmenopausal body size) have a 30% relative increase in breast cancer in comparison with what they would have if they did not have that risk factor. But the absolute increase in risk is based on the underlying absolute risk of disease. Figure 5 and Table 2 show the impact of a relative risk factor in the range of 1.3 on absolute risk. (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.) As shown, women with a family history of breast cancer have a much higher benefit from risk factor reduction on an absolute scale.[1]
Figure 5. These five pedigrees depict probands with varying degrees of family history. Table 2 accompanies this figure.
With the increasing use of multigene panel tests (see below), a framework for cancer risk management among individuals with pathogenic variants detected in novel genes has been described [2] that incorporates data on age-specific, lifetime, and absolute cancer risks. The framework suggests initiating screening in these individuals at the age when their 5-year cancer risk approaches that at which screening is routinely initiated for women in the general population (approximately 1% for breast cancer in the United States). As a result, the age at which to begin screening will vary depending on the gene.
Since the availability of next-generation sequencing and the Supreme Court of the United States ruling that human genes cannot be patented, several clinical laboratories now offer genetic testing through multigene panels at a cost comparable to single-gene testing. Even testing for BRCA1 and BRCA2 is a limited panel test of two genes. Approximately 25% of all ovarian/fallopian tube/peritoneal cancers are due to a heritable genetic condition. Of these, about one-quarter (6% of all ovarian/fallopian tube/peritoneal cancers) are caused by genes other than BRCA1 and BRCA2, including many genes associated with the Fanconi anemia pathway or otherwise involved with homologous recombination.[1] In a population of ovarian cancer patients who test negative for BRCA1 and BRCA2 pathogenic variants, multigene panel testing can reveal actionable pathogenic variants.[2,3] In an unselected population of breast cancer patients, the prevalence of BRCA1 and BRCA2 pathogenic variants was 6.1%, while the prevalence of pathogenic variants in other breast/ovarian cancerpredisposing genes was 4.6%.[4] A caveat is the possible finding of a variant of uncertain significance, where the clinical significance remains unknown. Many centers now offer a multigene panel test instead of just BRCA1 and BRCA2 testing if there is a concerning family history of syndromes other than hereditary breast and ovarian cancer, or more importantly, to gain as much genetic information as possible with one test, particularly if there may be insurance limitations.
(Refer to the Multigene [panel] testing section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about multigene testing, including genetic education and counseling considerations and research examining the use of multigene testing.)
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 the paternal lineage), sometimes including tumors of other organs, particularly the ovary and prostate gland.[1,2] It is now known that some of these cancer families can be explained by specific pathogenic variants in single cancer susceptibility genes. The isolation of several of these genes, which when altered 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 pathogenic variants 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.[3] 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.[4] 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.[5] 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 pathogenic variants in BRCA1 are associated with early-onset breast cancer, ovarian cancer, and fallopian tube cancer. (Refer to the Penetrance of BRCA pathogenic variants section of this summary for more information.) Male breast cancer, pancreatic cancer, testicular cancer, and early-onset prostate cancer may also be associated with pathogenic variants in BRCA1;[6-9] however, male breast cancer, pancreatic cancer, and prostate cancer are more strongly associated with pathogenic variants 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. Pathogenic variants 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.[8-14] (Refer to the Penetrance of BRCA pathogenic variants section of this summary for more information.) BRCA2 is a large gene with 27 exons that encode a protein of 3,418 amino acids.[15] 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 pathogenic variants, there is often loss of the wild-type allele.
Pathogenic variants 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.[16]
Most BRCA1 and BRCA2 pathogenic variants are predicted to produce a truncated protein product, and thus loss of protein function, although some missense pathogenic variants cause loss of function without truncation. Because inherited breast/ovarian cancer is an autosomal dominant condition, persons with a BRCA1 or BRCA2 pathogenic variant 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 carriers of pathogenic variants, 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.[17,18]
Nearly 2,000 distinct variants and sequence variations in BRCA1 and BRCA2 have already been described.[19] Approximately 1 in 400 to 800 individuals in the general population may carry a germline pathogenic variant in BRCA1 or BRCA2.[20,21] The variants 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 pathogenic variants have been found repeatedly in unrelated families, most have not been reported in more than a few families.
Variant-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 variants that are detected by DNA sequencing.[22] 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 variants but are less frequently seen in BRCA2 and in individuals of Ashkenazi Jewish (AJ) descent.[23-29] Furthermore, studies have suggested that these rearrangements may be more frequently seen in Hispanic and Caribbean populations.[27,29,30]
Germline pathogenic variants in the BRCA1/BRCA2 genes are associated with an approximately 60% lifetime risk of breast cancer and a 15% to 40% lifetime risk of ovarian cancer. There are no definitive functional tests for BRCA1 or BRCA2; therefore, the classification of nucleotide changes to predict their functional impact as deleterious or benign relies on imperfect data. The majority of accepted pathogenic variants result in protein truncation and/or loss of important functional domains. However, 10% to 15% of all individuals undergoing genetic testing with full sequencing of BRCA1 and BRCA2 will not have a clearly pathogenic variant detected but will have a variant of uncertain (or unknown) significance (VUS). VUS may cause substantial challenges in counseling, particularly in terms of cancer risk estimates and risk management. Clinical management of such patients needs to be highly individualized and must take into consideration factors such as the patients personal and family cancer history, in addition to sources of information to help characterize the VUS as benign or deleterious. Thus an improved classification and reporting system may be of clinical utility.[31]
A comprehensive analysis of 7,461 consecutive full gene sequence analyses performed by Myriad Genetic Laboratories, Inc., described the frequency of VUS over a 3-year period.[32] Among subjects who had no clearly pathogenic variant, 13% had VUS defined as missense mutations and mutations that occur in analyzed intronic regions whose clinical significance has not yet been determined, chain-terminating mutations that truncate BRCA1 and BRCA2 distal to amino acid positions 1853 and 3308, respectively, and mutations that eliminate the normal stop codons for these proteins. The classification of a sequence variant as a VUS is a moving target. An additional 6.8% of subjects with no clear pathogenic variants had sequence alterations that were once considered VUS but were reclassified as a polymorphism, or occasionally as a pathogenic variant.
The frequency of VUS varies by ethnicity within the U.S. population. African Americans appear to have the highest rate of VUS.[33] In a 2009 study of data from Myriad, 16.5% of individuals of African ancestry had VUS, the highest rate among all ethnicities. The frequency of VUS in Asian, Middle Eastern, and Hispanic populations clusters between 10% and 14%, although these numbers are based on limited sample sizes. Over time, the rate of changes classified as VUS has decreased in all ethnicities, largely the result of improved variant classification algorithms.[34] VUS continue to be reclassified as additional information is curated and interpreted.[35,36] Such information may impact the continuing care of affected individuals.
A number of methods for discriminating deleterious from neutral VUS exist and others are in development [37-40] including integrated methods (see below).[41] Interpretation of VUS is greatly aided by efforts to track VUS in the family to determine if there is cosegregation of the VUS with the cancer in the family. In general, a VUS observed in individuals who also have a pathogenic variant, especially when the same VUS has been identified in conjunction with different pathogenic variants, is less likely to be in itself deleterious, although there are rare exceptions. As an adjunct to the clinical information, models to interpret VUS have been developed, based on sequence conservation, biochemical properties of amino acid changes,[37,42-46] incorporation of information on pathologic characteristics of BRCA1- and BRCA2-related tumors (e.g., BRCA1-related breast cancers are usually estrogen receptor [ER]negative),[47] and functional studies to measure the influence of specific sequence variations on the activity of BRCA1 or BRCA2 proteins.[48,49] When attempting to interpret a VUS, all available information should be examined.
Statistics regarding the percentage of individuals found to be carriers of BRCA pathogenic variants 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 pathogenic variant likelihood based on additional personal and family history characteristics.
In some cases, the same pathogenic variant has been found in multiple apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant 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 pathogenic variants (185delAG and 5382insC) and a BRCA2 pathogenic variant (6174delT) have been reported to be common in AJs. However, other founder pathogenic variants have been identified in African Americans and Hispanics.[30,50,51] The presence of these founder pathogenic variants 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 pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants.[32]
Among the general population, the likelihood of having any BRCA variant is as follows:
Among AJ individuals, the likelihood of having any BRCA variant is as follows:
Two large U.S. population-based studies of breast cancer patients younger than age 65 years examined the prevalence of BRCA1 [55,70] and BRCA2 [55] pathogenic variants in various ethnic groups. The prevalence of BRCA1 pathogenic variants 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-AJ whites, and 8.3% to 10.2% in AJ individuals.[55,70] The prevalence of BRCA2 pathogenic variants by ethnic group was 2.6% in African Americans and 2.1% in whites.[55]
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 pathogenic variants. BRCA pathogenic variants were identified in 189 of 746 patients (25%) (124 BRCA1, 65 BRCA2);[71] 21 of the 189 (11%) BRCA pathogenic variants identified were large rearrangements, of which 13 (62%) were the BRCA1 exon 912 deletion. An unselected cohort of 810 women of Mexican ancestry with breast cancer were tested; 4.3% had a BRCA pathogenic variant. Eight of the 35 pathogenic variants identified also were the BRCA1 exon 912 deletion.[72] In another population-based cohort of 492 Hispanic women with breast cancer, the BRCA1 exon 912 deletion was found in three patients, suggesting that this variant may be a Mexican founder pathogenic variant and may represent 10% to 12% of all BRCA1 pathogenic variants in similar clinic- and population-based cohorts in the United States. Within the clinic-based cohort, there were nine recurrent pathogenic variants, which accounted for 53% of all variants observed in this cohort, suggesting the existence of additional founder pathogenic variants in this population.
A retrospective review of 29 AJ patients with primary fallopian tube tumors identified germline BRCA pathogenic variants in 17%.[69] Another study of 108 women with fallopian tube cancer identified pathogenic variants in 55.6% of the Jewish women and 26.4% of non-Jewish women (30.6% overall).[73] Estimates of the frequency of fallopian tube cancer in carriers of BRCA pathogenic variants are limited by the lack of precision in the assignment of site of origin for high-grade, metastatic, serous carcinomas at initial presentation.[6,69,73,74]
Population screening has identified carriers in a number of AJ populations who would not have met criteria for family-based testing.[62,75-77] This could potentially expand the number of individuals who could benefit from preventive strategies. Because the detection rate is highly dependent on the prevalence of pathogenic variants in a population, it is not clear how applicable this approach would be for other populations, including other founder pathogenic variant populations. Another unanswered question is whether adequate genetic counseling can be provided for whole populations.
Several studies have assessed the frequency of BRCA1 or BRCA2 pathogenic variants in women with breast or ovarian cancer.[55,56,70,78-86] Personal characteristics associated with an increased likelihood of a BRCA1 and/or BRCA2 pathogenic variant include the following:
Family history characteristics associated with an increased likelihood of carrying a BRCA1 and/or BRCA2 pathogenic variant include the following:
Several professional organizations and expert panels, including the American Society of Clinical Oncology,[91] the National Comprehensive Cancer Network (NCCN),[92] the American Society of Human Genetics,[93] the American College of Medical Genetics and Genomics,[94] the National Society of Genetic Counselors,[94] the U.S. Preventive Services Task Force,[95] and the Society of Gynecologic Oncologists,[96] have developed clinical criteria and practice guidelines that can be helpful to health care providers in identifying individuals who may have a BRCA1 or BRCA2 pathogenic variant.
Many models have been developed to predict the probability of identifying germline BRCA1/BRCA2 pathogenic variants in individuals or families. These models include those using logistic regression,[32,78,79,81,84,97,98] genetic models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]),[84,99] and empiric observations,[52,55,58,100-102] including the Myriad prevalence tables.
In addition to BOADICEA, BRCAPRO is commonly used for genetic counseling in the clinical setting. BRCAPRO and BOADICEA predict the probability of being a carrier and produce estimates of breast cancer risk (see Table 3). The discrimination and accuracy (factors used to evaluate the performance of prediction models) of these models are much higher for these models' ability to report on carrier status than for their ability to predict fixed or remaining lifetime risk.
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