INTRODUCTION —
Most females with breast or ovarian cancer have a sporadic rather than an inherited cancer. Although the majority of females with inherited breast and/or ovarian cancers carry a pathogenic variant (ie, deleterious or harmful mutation) in the breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2), some hereditary breast cancers are due to other rare hereditary syndromes, such as Li-Fraumeni and Cowden syndromes, which are associated with pathogenic variants in the tumor protein p53 (TP53) and phosphatase and tensin homolog tumor suppressor (PTEN) genes, respectively. Pathogenic variants in other genes also confer a heightened risk of breast and/or ovarian cancer.
This topic will present an overview of hereditary breast and ovarian cancer syndromes and risk reduction for breast and gynecologic cancers. However, risk reduction of other cancers associated with pathogenic variants in high-penetrance genes, as well as many of the moderate-penetrance genes, is discussed in other dedicated topics. In such instances, relevant links are provided in the sections below.
Additionally, details regarding who should be offered genetic risk evaluation, how the diagnosis of these syndromes should be made, as well as a more focused discussion of the BRCA1/2-associated hereditary breast and ovarian cancer syndromes are covered separately.
HIGH-PENETRANCE GENES —
Below we cover genes in which pathogenic variants confer high risks of breast and/or ovarian cancer, and other cancers. Specific management guidelines are available to manage patients and are briefly discussed here, with emphasis on the management of breast and gynecologic cancers.
BRCA1/BRCA2 — The most common pathogenic variants associated with hereditary breast and ovarian cancers occur in either the breast cancer type 1 or 2 susceptibility genes (BRCA1/2). Overall, pathogenic variants in these genes are implicated in approximately 15 percent of females with familial breast cancer and a similar proportion of all females with incident ovarian cancers. Cancer risks and management of BRCA1/2 carriers is discussed in detail elsewhere.
TP53 (Li-Fraumeni syndrome) — Li-Fraumeni syndrome (LFS) is associated with germline pathogenic variants in the tumor protein p53 gene (TP53), and carriers are at increased risk of developing multiple primary cancers in childhood or young adulthood, including sarcomas, central nervous system tumors, leukemias, medulloblastoma, and adrenocortical cancers [1-3]. Discussion on the clinical manifestations, surveillance, and management of those with LFS is found elsewhere. (See "Li-Fraumeni syndrome", section on 'Cancer surveillance strategy' and "Li-Fraumeni syndrome", section on 'Management'.)
STK11 (LKB1, Peutz-Jeghers syndrome) — Peutz-Jeghers syndrome (PJS) is a rare disorder associated with pathogenic variants in the serine/threonine kinase 11 gene (STK11, also called LKB1) [4]. Mucocutaneous pigmented lesions occur in approximately 95 percent of affected patients; additionally, hamartomatous polyps in the gastrointestinal tract are hallmark features [5]. This syndrome is associated with very elevated risks for gastrointestinal cancers, including cancers of the colon and rectum, stomach, small intestine, and pancreas, as well as breast and ovarian cancers, although ovarian cancers are often sex-cord stromal tumors, which are nonepithelial in origin [5]. Further discussion of PJS is covered separately. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
PTEN (PTEN hamartoma tumor syndrome) — The phosphatase and tensin homolog tumor suppressor gene (PTEN) hamartoma tumor syndrome (PHTS) includes Cowden syndrome, which is the predominant disorder. All are associated with germline pathogenic variants in the PTEN gene [6]. Carriers have elevated risks for breast, endometrial, and thyroid cancer, particularly follicular cancer [7], and possibly ovarian cancer [8].Management of other cancer risks associated with PTEN pathogenic variants is discussed elsewhere. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Management'.)
CDH1 (Hereditary diffuse gastric cancer syndrome) — Hereditary diffuse gastric cancer (HDGC) is characterized by a susceptibility to diffuse, highly invasive gastric cancer (also called signet ring carcinoma or isolated cell-type carcinoma) [9]. It is associated with germline pathogenic variants in the cadherin 1 gene (CDH1) [10,11]. Germline CDH1 mutations are also associated with development of lobular breast cancer in females [9-13].
Management of risks is discussed elsewhere. (See "Diffuse gastric and lobular breast cancer syndrome", section on 'Management of carriers of CDH1 variants'.)
PALB2 — Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that encodes a BRCA2-interacting protein [14,15] (table 1). The BRCA2-PALB2 interaction is crucial for key BRCA2 deoxyribonucleic acid (DNA) damage response functions as well as tumor suppression activity [16,17].
●Risks – The cumulative lifetime breast cancer risk to age 80 for all female carriers is approximately 53 percent, whereas the cumulative risk to age 50 is approximately 17 percent [18]. In two large cohort studies, there was a greater association for estrogen receptor (ER)-negative breast cancer than for ER-positive breast cancer among PALB2 carriers [19,20]; for example, in one study, the odds ratios relative to noncarriers were 9.2 for ER-negative cancers and 3.1 for ER-positive cancers [20].
In comparison with the general population, the relative risk of breast cancer for a female with a PALB2 pathogenic variant based upon her age is [21]:
•Under 40 years – Eight- to ninefold increase
•40 to 60 years – Six- to eightfold increase
•Over 60 years – Fivefold increase
Given this range of risk, and that the upper risk range can overlap with BRCA2 risks, PALB2 is considered to be a high-risk gene associated with hereditary breast cancer [21-24]. Breast cancer risk associated with a PALB2 pathogenic variant appears to be influenced by birth cohort, a family history of breast cancer, and other as yet unidentified environmental and lifestyle factors [18,21]. In an international study of 524 families with a PALB2 pathogenic variant, the absolute lifetime risk to age 70 years for the development of female breast cancer was dependent upon family history of breast cancer, as follows [21]:
•No family history of breast cancer – 33 percent
•Two or more family members with breast cancer – 58 percent
For females with a premenopausal diagnosis of ER-negative breast cancer only, the risk of contralateral breast cancer at 15 years has been reported to be 36 percent (95% CI, 15-84 percent) [25]. As the wide confidence interval reflects, this estimate is based on only four cases. There did not appear to be an elevated risk of contralateral breast cancer among the 20 premenopausal ER-positive PALB2 carriers or the 61 females with postmenopausal breast cancer.
Separately, an international study of 524 families reported a risk of male breast cancer of 0.9 percent for males born between 1950 to 1959 (95% CI, 0.2 to 4.9 percent) [18]. Additional research will further define the risks in males.
Although rare, PALB2 pathogenic variants are present in a small but substantial proportion of patients with breast cancer [21,26], including approximately 1 percent of patients with breast cancer and approximately 1 percent of patients with triple-negative breast cancer [27,28]. In high-risk families, pathogenic PALB2 variants were identified in 3.9 percent (13 of 409) of breast and/or ovarian cancer patients in the Czech Republic who were negative for BRCA1/2 mutations [29].
Several studies have shown that PALB2 pathogenic variants are associated with an elevated risk of ovarian cancer compared with the general population, but the absolute risk is overall low (on the order of 3 to 5 percent) [7,18,30,31]. Pathogenic variants are also associated with an increased risk of pancreatic cancer (2 to 5 percent), although the absolute risk is unclear [7,18,32,33]. In addition, there may also be an association with increased risks for breast cancer in males (approximately 1 percent), prostate cancer, and medulloblastoma, although these risks are not confirmed and are difficult to quantify [7,18,30,34-37].
Biallelic mutations in the PALB2 gene, also known as FANCN, cause Fanconi anemia [7,38]. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)
●Management – For females with pathogenic variants in PALB2, we initiate annual mammography with tomography and annual breast magnetic resonance imaging (MRI), with and without contrast starting at age 30 years or 5 to 10 years prior to the youngest diagnosis of breast cancer in the family, whichever comes first [7]. We also discuss the option of risk-reducing mastectomy, particularly for females with a strong family history of breast cancer [7]. There are no data about efficacy of hormonal chemoprevention (tamoxifen or aromatase inhibitor); moreover, studies have found that there is an increased risk of triple-negative breast cancer in PALB2 carriers. Therefore, the benefits of this approach are unknown in PALB2 carriers.
Additionally, we discuss the option of risk-reducing bilateral salpingo-oophorectomy (rrBSO) for carriers starting at age 45 to 50 years [7]. When females have a family history of ovarian cancer, we suggest that they undergo rrBSO.
In male PALB2 carriers, starting at age 35, the following is appropriate [7]:
•Training and education about breast self-examination
•Annual clinical breast examination
•Consideration of annual mammography starting at age 50 or if there is male breast cancer in the family, 10 years earlier than the earliest diagnosis
Screening for pancreatic cancer in PALB2 carriers with relevant family history is discussed elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Screening modality and timing'.)
MSH2, MLH1, MSH6, PMS2, and EPCAM (Lynch syndrome)
●Risks – Lynch syndrome, also called hereditary nonpolyposis colon cancer, is associated with pathogenic variants in mismatch repair (MMR) genes (MSH2, MLH1, MSH6, and PMS2) and pathogenic variants in the epithelial cell adhesion molecule gene (EPCAM) [39-41]. These variants carry risks of colon, endometrial, ovarian, and stomach cancer. Although some studies have suggested that there is an increased risk of breast cancer associated with Lynch syndrome, the data are inconclusive [42]. The discussion of Lynch syndrome is covered separately. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer", section on 'Candidates' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management".)
Screening for other cancers in patients with Lynch syndrome (eg, pancreatic, in those with a family history) is discussed elsewhere. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Screening for Lynch-associated cancers'.)
MODERATE-PENETRANCE GENES
General considerations — In addition to well-described familial syndromes and high-penetrance gene variants associated with an increased risk of breast and/or ovarian cancer, pathogenic variants in other genes at least moderately increase the risk of these cancers [19,20].
●Risks – Females who have pathogenic variants in neurofibromatosis type 1 (NF1), ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2), or breast cancer susceptibility gene 1 (BRCA1)-associated RING domain 1 (BARD1) have a moderate lifetime risk of breast cancer, and those with mutations in RAD51 paralog C (RAD51C) or RAD51 paralog D (RAD51D) have a moderate lifetime risk for breast or ovarian cancer, and as such are managed with surveillance and risk reduction strategies. Estimated average five-year and cumulative breast cancer risks for females with pathogenic variants in moderate to high penetrance are useful for counseling purposes (table 1) [19,20,24].
Several large case-control studies have described the associations between a number of possible cancer susceptibility genes and the risk of breast cancer [27,39]. As examples:
•Two large case-control studies have described the associations between a number of possible cancer susceptibility genes and the risk of breast cancer. The international study included 113,000 females from 25 countries, and evaluated 34 genes [19]; separately, 28 genes were evaluated in 64,000 females from the United States [20]. Aside from BRCA1 and breast cancer susceptibility gene 2 (BRCA2), variants in PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were associated with breast cancer risk in both studies. Variants in other genes such as NBN1 and MUTYH were not found to be associated with an increased risk for breast cancer. Lifetime risks of several commonly mutated genes are shown in the figure (figure 1).
•These studies also quantified the risk of estrogen receptor (ER)-positive and ER-negative breast cancers (table 2 and figure 2).
Given the size and design of these studies, these studies provide the most comprehensive assessment of risk to date.
Cancer risks for pathogenic variants in other genes are less well established. Commercial multigene panels include testing for the BRCA1/2 genes, the high-risk genes listed above, as well as several moderate-risk genes and newer genes with preliminary evidence for associations with heightened cancer risks.
Patients who test positive for a pathogenic variant or a variant of uncertain significance in these and other rare cancer susceptibility genes may participate in an online registry called Prospective Registry of Multiplex Testing, a collaborative effort among academic institutions and commercial labs in the United States to learn more about how to interpret these results [43,44].
●Considerations regarding surveillance and risk management – Decisions about chemoprevention and risk-reducing mastectomy (RRM) and/or salpingo-oophorectomy should be highly individualized based on the female's mutation status as well as personal and family history. Individualized recommendations should also take into account the patient's personal risk factors and family history, which may affect the age that screening modalities start (eg, 5 to 10 years before the earliest age of breast cancer diagnosis in the family), whether MRI is recommended, and whether mastectomy is offered. For females with pathogenic variants in other genes that are not known to be associated with increased risks for breast cancer, if models estimate their lifetime risk of breast cancer is 20 percent or higher, MRI screening is recommended [45]. Some such females may also be candidates for chemoprevention against breast cancer, depending on their personal and family history. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
With respect to ovarian cancer screening in females with pathogenic variants in the moderate-penetrance genes, we typically do not recommend either imaging or cancer antigen 125 measurements given the limited efficacy; however, we may recommend risk-reducing bilateral salpingo-oophorectomy (rrBSO) for some patients based on their genetic testing results, such as for RAD51C carriers. (See 'RAD51 paralogs' below.)
CHEK2 — The checkpoint kinase 2 (CHEK2) gene is associated with the DNA damage repair response Fanconi anemia (FA)-BRCA1/2 pathway [46,47]. (See "Gene test interpretation: CHEK2".)
●Risks – Studies have found that CHEK2 carriers have increased risks for breast cancer (particularly ER-positive breast cancers), male breast cancer, stomach, prostate, kidney, leukemia, plasma cell neoplasms, thyroid cancer, and sarcoma [48-50]. Although some studies found that specific CHEK2 variants have been associated with an increased lifetime risks of colorectal cancer (11 percent in 1100delC carriers; 9 percent in I157T carriers) [51], a recent large study of 3783 CHEK2 carriers, including those with 1100delC and I157T, found no increased risk [52]. There is no strong evidence that CHEK2 mutations confer an increased risk of ovarian cancer given how infrequently they are identified in females with ovarian cancer [30,53].
It is critical to review the genetic testing report carefully (algorithm 1). Risk information and associated management recommendations for variants in the CHEK2 gene may be dependent on the specific variant identified.
Several CHEK2 variants have been identified [52,54], including one polymorphism (1100delC) that appears to be associated with a low- to moderate-penetrance breast cancer susceptibility allele [48,52,54-60].
•1100delC protein-truncating variant – The 1100delC protein-truncating variant is associated with a two- to threefold increased risk of breast cancer, particularly hormone receptor-positive cancer, and occurring predominantly among White Americans and people from Northern or Eastern Europe [48,61-66]. The cumulative risk of breast cancer has been estimated to be 37 percent by age 70 years [67] and 32 percent by age 80 in another study [24]. The latter study estimated a 6 percent cumulative risk to age 49.
There are several significant differences between mutation carriers and noncarriers with breast cancer. For example, in one study, compared with noncarriers, CHEK2 carriers of the 100delC variant were significantly more likely to [63]:
-Be younger at the time of diagnosis (mean age, 50 versus 54)
-Have a family history of breast cancer (13 versus 10 percent)
-Develop ER-positive breast cancers (63 versus 57 percent)
-Develop a second primary breast cancer (hazard ratio [HR] 3.52, 95% CI 2.35-5.27), a risk which is higher among females whose first breast cancer was ER-positive
•Other variants – A large retrospective cohort study of 3783 participants found that certain missense variants in CHEK2 (I157T, S428F, and T476M), which occurred in 42 percent of the sample, were associated with a lower risk of breast cancer than the 1100delC protein-truncating variant and were not associated with risks for other types of cancer [52]. Similarly, a meta-analysis of 18 case-control studies found that the I157T variant is associated with only a modest increase in breast cancer risk (odds ratio [OR] 1.58, 95% CI 1.42-1.75) [68]. Estimated age-specific risks for the I157T variant indicate that the cumulative lifetime risk of breast cancer to age 80 is approximately 18 percent, whereas the cumulative risk of breast cancer to age 49 is approximately 3 percent [24].
Family history of breast cancer has been shown to impact breast cancer risk in CHEK2 carriers [66]. An international study of over 26,000 breast cancer cases and 26,000 controls suggested that polygenic risk score modulated breast cancer risk. By age 80, CHEK2 carriers with no family history of breast cancer had a 15 percent likelihood of breast cancer if they were in the 10th percentile for polygenic risk scores (PRS), whereas their risk was 37 percent if they were in the 90th percentile for PRS [69].
Prospective data from one study show that among premenopausal CHEK2 carriers the 10-year cumulative risk of contralateral breast cancer is 13 percent, and 4 percent for postmenopausal patients [25]. These percentages include the 1100delC and other truncating variants. It is unclear whether missense variants increase the risk of contralateral breast cancer.
●Management – For those with pathogenic variants in CHEK2, we typically initiate annual mammography with tomography at age 40 years and offer annual MRI, with and without contrast, starting at age 30 to 35 years, given evidence of moderately increased lifetime risk of breast cancer. The age to initiate breast cancer screening is modified based on family history and should begin 5 to 10 years earlier than the youngest breast cancer diagnosis in the family, but no later than age 30 to 35 years. There is insufficient risk to support a recommendation for RRM, although it may be reasonable to consider this option for those with a concerning family history or other risk factors (eg, atypia or a breast cancer diagnosis) [7,70].
For select females at increased risk for breast cancer, chemoprevention with endocrine therapy may be an appropriate option, particularly as females with CHEK2 mutations are more likely to develop ER-positive breast cancers [71]. However, no data are available regarding efficacy specifically in this group of mutation carriers. (See "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
Pathogenic variants in CHEK2 do not appear to confer a significantly increased risk for ovarian cancer. For carriers who have a family history of ovarian cancer, we discuss the potential risks and benefits of rrBSO. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)
Given that data about the risk of colorectal cancer are conflicting, national guidelines recommend management based on personal risk factors and family history of colorectal cancer, and we agree with this approach [72].
Shared decision making between male CHEK2 carriers and their clinicians regarding prostate cancer screening should begin at age 40 years [7].
ATM — Heterozygotes for a single pathogenic ATM variant are at increased risk for some cancers (algorithm 2). (See "Gene test interpretation: ATM (ataxia-telangiectasia, breast cancer, and pancreatic cancer susceptibility gene)".)
●Risks – Monoallelic carriers of such pathogenic variants (ie, heterozygotes) are at approximately twofold higher risk of developing breast cancer than noncarriers, with a cumulative lifetime breast cancer risk of approximately 20 to 40 percent (and 6 percent to age 49) [7,24,73-77]. In two large cohort studies, there was a greater association for ER-positive breast cancer than for ER-negative breast cancer, among ataxia-telangiectasia mutated (ATM) carriers [19,20]; for example, the OR was approximately 2.0 to 2.3 for ER-positive disease in carriers relative to the noncarriers (versus approximately 1.0 for ER-negative disease). Rare pathogenic variants in the ATM gene may be associated with a substantially higher risk of breast cancer, so risk assessment based on genotype can be important [74,75]. The risk of second primary breast cancer is not clear [78]. Although it is also possible that there is an increased risk of ovarian cancer based on results of a case-control study [39], these data need to be confirmed.
It is estimated that approximately 3 percent of White people in the United States are ATM heterozygotes [79]. In a retrospective study of 443 BRCA1/2-negative familial breast cancer patients and 521 control breast cancer patients, ATM mutations were more commonly identified in patients with familial breast cancer compared with the control population (12 versus 2 deleterious ATM mutations) [73]. Relatives of individuals with AT, especially obligate carrier mothers of affected children, should be informed about the elevated cancer risks and potential screening strategies.
ATM pathogenic variants have also been associated with increased risks for pancreatic cancer [50,80], with an absolute risk estimated at 5 to 10 percent [7]. There may also be somewhat higher risks of ovarian cancer, prostate cancer, and gastric cancer, but more data are needed to confirm these findings [39,50]. The potential increased risk for this and other cancers has not been well characterized. (See "Gene test interpretation: ATM (ataxia-telangiectasia, breast cancer, and pancreatic cancer susceptibility gene)", section on 'Monoallelic ATM disease variant (AT carrier)'.)
In regards to noncancer risks, heterozygotes for a single pathogenic ATM variant are also at possibly higher risk of coronary artery disease [81].
Pathogenic biallelic variants in the ATM gene give rise to AT. AT is discussed in more detail separately. (See "Ataxia-telangiectasia".)
●Management – For those with pathogenic variants in ATM, we typically initiate annual mammography with tomography at age 40 years, and offer annual MRI, with and without contrast, starting at age 30 to 35 years, given evidence of moderately increased lifetime risk of breast cancer [7]. In light of the higher risk of breast cancer associated with the c.7271T>G variant, surveillance may begin at age 25 with breast MRI and the addition of annual mammography beginning at age 30 [81]. There is insufficient risk to support a recommendation for RRM, although for those with a concerning family history or other risk factors (eg, atypia or a diagnosis of breast cancer), it may be reasonable for carriers to consider this option [7]. Breast surveillance recommendations may be modified based on genotype and family history [81].
Pathogenic variants in ATM do not appear to confer a significantly increased risk for ovarian cancer. For carriers who have a family history of ovarian cancer, we discuss the potential risks and benefits of rrBSO. (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)
For ATM carriers with a family history of pancreatic cancer, pancreatic cancer screening is offered. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Screening modality and timing'.)
Given emerging evidence for an association with prostate cancer, we offer prostate cancer screening to male carriers starting at 40 years [82]. (See "Screening for prostate cancer".)
●Considerations for ATM carriers with cancer – We generally do not alter our approach to radiation therapy or chemotherapy in individuals who are ATM heterozygotes and warrant such treatments. While patients with AT are particularly sensitive to ionizing radiation and chemotherapeutic agents that cause double-stranded breaks in DNA, ATM heterozygotes are less sensitive [83]. Preliminary evidence from one observational study of 91 ATM mutation carriers receiving radiation for breast cancer did not suggest high rates of toxicity, irrespective of whether the mutations were pathogenic or variants of unknown significance [84]. The clinical impact of such issues is not well known, and, in general, we treat ATM heterozygotes with cancer with the "best" standard therapies for their particular cancer, and do not withhold radiation, when indicated [81,85].
Of note, in one prospective study, the risk of contralateral breast cancer was not elevated in heterozygous ATM carriers [25].
BARD1 — BRCA1-associated RING domain 1 (BARD1) is involved in the FA-BRCA1/2 pathway (see 'CHEK2' above). Pathogenic variants in this gene are rare.
●Risks – Pathogenic variants in BARD1 predispose to an increased risk of breast cancer in females on the order of 17 to 30 percent [7,19]. In two large cohort studies, there was a greater association for ER-negative breast cancer than for ER-positive breast cancer among BARD1 carriers [19,20]; for example, in one study, the ORs relative to noncarriers were 2.5 for ER-negative cancers and 0.9 for ER-positive cancers [20]. There does not appear to be a definitive association with ovarian cancer risk [30,86-88].
●Management – For those with pathogenic variants in BARD1, we initiate annual mammograms at age 40, along with consideration of breast MRI with and without contrast [7]. There is insufficient risk to support a recommendation for RRM, although for those with a concerning family history or other risk factors (eg, atypia or a diagnosis of breast cancer), it may be reasonable for carriers to consider this option. (See "Screening for breast cancer: Strategies and recommendations", section on 'Breast cancer risk determination'.)
RAD51 paralogs — Related genes in the same family are called paralogs, and the RAD51 paralogs, RAD51 paralog C (RAD51C) and RAD51 paralog D (RAD51D), are involved in the FA-BRCA1/2 pathway. Therefore, carriers should be aware of reproductive implications if their partner is also found to have a similar pathogenic variant.
●Risks – RAD51C and RAD51D mutations are rare and confer an increased risk of ovarian cancer, as well as an increase in breast cancer, especially for triple-negative breast cancers [7,19,20,89-97]. The absolute risk of breast cancer is estimated to be between 17 to 30 percent [7,19,97]. However, not all studies have demonstrated increased breast cancer risks [98].
•Breast cancer risks – In two large cohort studies, there was a greater association for ER-negative breast cancer than for ER-positive breast cancer among carriers of pathogenic variants in RAD51 paralogs [19,20]; for example, in one study, the ORs relative to noncarriers were 9.2 for ER-negative cancers and 3.1 for ER-positive cancers [20]. In addition, breast cancer risks in RAD51C and RAD51D carriers could be as high as 44 to 46 percent if they have two first-degree relatives with breast cancer [97]. No data are available about the risk of contralateral breast cancer.
•Ovarian cancer risks – RAD51C and RAD51D pathogenic variants have been reported in 0.67 percent of ovarian cancer patients unselected for family history [90]. Several studies have established that pathogenic variants in these two genes are associated with at least a fivefold increased risk for ovarian cancer [90,97,99]. In one study of 6178 families with 125 RAD51C carriers and 6690 families with 60 RAD51D carriers the estimated risk of tubo-ovarian cancer to age 80 years was 11 percent (95% CI, 6-21 percent) and 13 percent (95% CI, 7-23 percent), respectively [97]. In that study, carriers who had two first-degree relatives with tubo-ovarian cancer had ovarian cancer risks as high as 32 to 36 percent. Of note, the risk of ovarian cancer in carriers of either gene is low, at approximately 1 percent by age 50 [24,90].
●Management – For those with pathogenic variants in RAD51 paralogs, we initiate annual mammogram and offer breast MRI, with and without contrast, starting at age 40 years [7]. The evidence is insufficient to uniformly recommend RRM, although for those with a concerning family history or other risk factors (eg, atypia or a diagnosis of breast cancer), it may be reasonable for carriers to consider this option [7].
rrBSO is recommended between age 45 to 50 years, or earlier if there is a family history of ovarian cancer, particularly if the age of onset was early [7]. We inform females that, although there are no data in these gene carriers, use of oral contraceptives may reduce the risk of ovarian cancer, as observed in females with pathogenic variants in BRCA1/2 [100].
NF1 — Pathogenic variants in neurofibromatosis type 1 (NF1) give rise to neurofibromatosis 1 [101,102], an autosomal dominant syndrome in which affected individuals develop café-au-lait macules, axillary and/or inguinal freckling, peripheral neurofibromas, optic pathway gliomas, soft tissue gliomas, and sarcomas. NF1 encodes for neurofibromin. Neurofibromin is a member of a family of proteins that affect a number of signaling pathways stimulating cell survival and proliferation [103-105]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)
Females with NF1 have an increased risk of early-onset breast cancer (generally between age 30 to 40), and do not appear to have an increased risk after age 50 [106,107]. These cancers tend to be associated with poorer survival than the general population [106,107].
Although the lifetime risk of cancer in people with NF1 is approximately 60 percent [106], the lifetime breast cancer risk in females is estimated to be between 20 to 40 percent [7].
Females with NF1 are recommended to begin annual mammography at age 30, and from age 30 to 50 years, consider breast MRI with and without contrast [7].
Because of the phenotypic associations with NF1, most affected individuals have previously received a clinical diagnosis. They are usually followed by a clinical geneticist. If multigene panel testing incidentally identifies an NF1 carrier who has not had a clinical diagnosis, we would make such a referral and coordinate their care for cancer risk management as needed. (See "Neurofibromatosis type 1 (NF1): Management and prognosis".)
BRIP1 — BRCA-interacting protein 1 (BRIP1) is a DNA repair gene that interacts with BRCA1. Biallelic germline mutations of this gene result in Fanconi anemia complementation groups [108].
●Risks – BRIP1-inactivating truncating mutations are hypothesized in several but not all studies to be associated with a slightly increased risk of breast cancer, and have more consistently been linked with a moderately increased risk of ovarian cancer [87,109-113]. Pathogenic variants have been identified in 1.4 percent of females with ovarian cancer [114]. In a case-control study of 3200 females with ovarian cancer, 3400 healthy controls, and 2000 unaffected females at high risk for ovarian cancer, BRIP1 was associated with an increased risk of ovarian cancer (relative risk [RR] 11.2) [87]. The cumulative lifetime risk of ovarian cancer to age 80 ranges between approximately 5 and 15 percent depending on the study methodology [24].
●Management – For those with pathogenic variants in BRIP1, we recommend rrBSO at age 45 to 50 years, per National Comprehensive Cancer Network guidelines [7]. We inform females that, although there are no data in these gene carriers, use of oral contraceptives may reduce the risk of ovarian cancer, as observed in females with pathogenic variants in BRCA1/2 [100].
Given that breast cancer risks are not well defined, no guidelines exist about how to manage breast cancer risks in females with pathogenic variants in newly identified genes, including BRIP1. In such cases, breast cancer risk should still be assessed based on personal and family history.
GENES PREVIOUSLY THOUGHT TO BE IMPLICATED IN BREAST CANCER
BRIP1 — BRCA-interacting protein 1 (BRIP1)-inactivating truncating mutations were previously thought to increase risk of breast cancer [115], but more recent and definitive large case-control studies found no increased risk for breast cancer [19,20,116]. There appears to be a stronger link to ovarian cancer. (See 'BRIP1' above.)
MUTYH — mutY DNA glycosylase (MUTYH) is a DNA base repair gene that corrects oxidative DNA damage, a critical function to maintain genomic stability and modulate carcinogenesis [117]. While some prior studies have suggested that MUTYH heterozygotes have an increased risk of breast cancer [118-120], more recent and definitive large case-control studies found no increased risk for breast cancer [19,20,116], although one has suggested an increased risk of kidney cancer [50]. We do not perform early mammography or breast MRI, unless their family history places them at increased risk.
Homozygous and biallelic carriers have an increased risk of colorectal polyposis and cancer [121-124]. (See "MUTYH-associated polyposis", section on 'Colorectal cancer surveillance'.)
NBN — NBN encodes the protein nibrin, which is involved with repair of DNA breaks, telomere maintenance, and base excision repair [125-132]. The most common pathogenic variant in patients of Eastern European descent is hypomorphic, leading to a partially functional protein [133]. Other mutations are more common in different populations [134]. Nijmegen breakage syndrome is an autosomal-recessive disorder caused by pathogenic variants in nibrin and is discussed elsewhere. (See "Nijmegen breakage syndrome".)
While some prior studies have suggested that NBN variant carriers have an increased risk of breast cancer [135,136], the more recent and definitive large population-based case-control studies found no increased risk for breast cancer [19,20]. Other studies also failed to demonstrate an association between pathogenic variants in NBN and breast cancer [27,137]. We do not perform early mammography or breast MRI, unless their family history places them at increased risk. (See 'Moderate-penetrance genes' above.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary breast and ovarian cancer" and "Society guideline links: Breast cancer".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Genetic testing for breast, ovarian, prostate, and pancreatic cancer (The Basics)" and "Patient education: Genetic testing (The Basics)")
●Beyond the Basics topics (see "Patient education: Genetic testing for hereditary breast, ovarian, prostate, and pancreatic cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Introduction – The majority of females who test positive for a gene associated with hereditary breast and/or ovarian cancers carry a pathogenic variant in the breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2). However, pathogenic variants in certain other genes also confer a heightened risk of breast and/or ovarian cancer. (See 'Introduction' above.)
●High-penetrance genes – Many of these high-risk syndromes have characteristic presentations, although more widespread use of multigene panel testing has shown that there can be significant variability, and not all individuals who test positive meet established diagnostic criteria for these other syndromes. (See 'High-penetrance genes' above.)
•Select cancer syndromes – Cancer risk management in patients with BRCA1/2 alterations, Li-Fraumeni syndrome, Peutz-Jeghers syndrome, phosphatase and tensin homolog tumor suppressor (PTEN) hamartoma tumor syndrome, hereditary diffuse gastric cancer syndrome, and Lynch syndrome are discussed elsewhere. Risk reduction strategies and/or early breast cancer screening and supplemental screening with breast MRI are appropriate in some of these syndromes. (See "Cancer risks in BRCA1/2 carriers" and "Li-Fraumeni syndrome", section on 'Cancer surveillance strategy' and "Li-Fraumeni syndrome", section on 'Cancer management' and "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management" and "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cancer surveillance' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Cancer screening and management", section on 'Candidates for screening' and "Diffuse gastric and lobular breast cancer syndrome", section on 'Surveillance for breast cancer'.)
•PALB2 – For females with pathogenic variants in partner and localizer of BRCA2 (PALB2), we initiate annual mammography with tomography and annual bilateral breast MRI, with and without contrast, starting at age 30 years or 5 to 10 years prior to the youngest diagnosis of breast cancer in the family, whichever comes first. We also discuss the option of risk-reducing mastectomy (RRM). Pathogenic variants in PALB2 are associated with a heightened risk for estrogen receptor (ER)-negative breast cancers.
For PALB2 carriers starting at age 45 to 50 years, risk-reducing bilateral salpingo-oophorectomy (rrBSO) is an appropriate option, given a small absolute increased risk in ovarian cancer, which may be further elevated in the setting of a family history of ovarian cancer. (See 'PALB2' above.)
●Moderate-penetrance genes – Pathogenic variants in other genes also contribute to increased risks for breast, ovarian, and other cancers. These genes are included on extended multigene panels. (See 'Moderate-penetrance genes' above.)
•Females who have pathogenic variants in the genes checkpoint kinase 2 (CHEK2) and ataxia-telangiectasia mutated (ATM) have a moderate to high lifetime risk of breast cancer, particularly ER-positive breast cancers, while BRCA1-associated RING domain 1 (BARD1) and the RAD51 paralogs confer a heightened risk of breast cancers that are more commonly ER-negative.
-Screening – For those with pathogenic variants in ATM or CHEK2, we initiate annual mammography with tomography at age 40 years and offer annual breast MRI with and without contrast. The age to initiate breast cancer screening is modified based on family history and should begin 5 to 10 years earlier than the youngest breast cancer diagnosis in the family, but no later than age 30 to 35 years.
-For those with pathogenic variants in RAD51 paralogs (RAD51C and RAD51D) or BARD1, we initiate annual mammogram and offer breast MRI with and without contrast. The age at which screening may be initiated may depend on the age at diagnosis of relatives with breast cancer, but should not start after age 40.
-Breast cancer risk reduction – ATM, CHEK2, neurofibromatosis type 1 (NF1), RAD51C and RAD51D carriers are not considered to be at sufficient risk to recommend RRM, although individual females may also consider it based on their personal and family history.
-Ovarian cancer risk reduction – For those with pathogenic variants in BRCA-interacting protein 1 (BRIP1), RAD51C, or RAD51D we suggest rrBSO beginning when the patient is 45 to 50 years, given evidence for increased ovarian cancer risks (Grade 2B). (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer".)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Suzanne W Fletcher, MD, who contributed to an earlier version of this topic review.
51 : An updated counseling framework for moderate-penetrance colorectal cancer susceptibility genes.
133 : Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome.