INTRODUCTION — Most women with breast or ovarian cancer have a sporadic rather than an inherited cancer. Although the majority of women with inherited breast and/or ovarian cancers carry a pathogenic variant (ie, deleterious or harmful mutation) in 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 the 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 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.
●(See "Cancer risks and management of BRCA1/2 carriers without cancer".)
HIGH-PENETRANCE GENES — Below we cover syndromes that confer high risks of breast and/or ovarian cancer, and other cancers. Specific management guidelines are available to manage patients with these syndromes and are briefly discussed here, with more detail provided in topics devoted to each specific syndrome.
Associated with multiple cancers
TP53 (Li-Fraumeni syndrome)
●Risks – 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 [1-3]. Overall, women have a lifetime cancer risk approaching 100 percent, although their risk is not exclusively associated with a heightened breast cancer risk. Associated malignancies aside from breast cancer include sarcomas, brain cancer, leukemias, medulloblastoma, and adrenocortical cancers. Although ovarian, fallopian tube, and peritoneal cancers have not been widely reported in families with LFS, TP53 mutations have been identified in women with these cancers [4], and one large case-control study suggested an association between TP53 mutations and ovarian cancer [5].
Women with LFS are at high risk for premenopausal breast cancer versus breast cancer later in life. While the lifetime risk of breast cancer development for female mutation carriers approaches 50 percent by age 60 years, the mean age of onset is under 35 years, and a first diagnosis of breast cancer is rare over age 50 years [2,3,6-10]. Between 64 and 83 percent of breast cancers in these carriers are positive for human epidermal growth factor receptor 2 (HER2) [11]. In addition, carriers are at increased risk of developing secondary malignancies in radiation fields [12]. Therefore, female carriers with breast cancer who receive radiotherapy are at increased risk for new primaries, especially within the breast, as well as radiation-induced cancers [13].
●Management – Women with LFS are typically offered risk-reducing mastectomy (RRM), although some may opt instead for early breast cancer screening supplemented with magnetic resonance imaging (MRI). We offer risk-reducing bilateral salpingo-oophorectomy (rrBSO) to carriers who have a family history of ovarian cancer [14]. Further discussion on the surveillance and management of those with LFS is found elsewhere. (See "Li-Fraumeni syndrome", section on 'Cancer surveillance strategy'.)
Women with LFS who develop breast cancer are generally recommended to undergo mastectomy, rather than lumpectomy and radiation, given the risks of radiation-induced malignancies in this syndrome [15]. Other clinical manifestations of LFS, and management of other cancer risks, are discussed separately. (See "Li-Fraumeni syndrome", section on 'Management'.)
STK11 (LKB1, Peutz-Jeghers syndrome)
●Risks – Peutz-Jeghers syndrome (PJS) is a rare disorder associated with pathogenic variants in the serine/threonine kinase 11 gene (STK11, also called LKB1) [16]. Mucocutaneous pigmented lesions occur in approximately 95 percent of affected patients; additionally, hamartomatous polyps in the gastrointestinal tract are hallmark features [17]. 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 [17].
The absolute risk of breast cancer is approximately 55 percent and, in general, the diagnosis tends to occur in younger women, with a mean age of 37 years (range, 9 to 48 years) [17,18].
For ovarian cancer, the prevalence in one study was 21 percent among patients with PJS, diagnosed at a mean age of 28 years (range, 4 to 57 years) [17]. Further discussion of PJS is covered separately. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
●Management – Women with PJS are offered early breast cancer screening with supplemental MRI. The evidence is insufficient to uniformly recommend RRM, although for those with a concerning family history (>20 percent risk of breast cancer by a model), it may be reasonable for carriers to consider this option. Models to determine risk of breast cancer are discussed elsewhere. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes", section on 'Risk assessment models'.)
Screening for endometrial and ovarian cancer in women with PJS is controversial. Further discussion of screening for these and other cancers in individuals with PJS is found elsewhere. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)
PTEN (PTEN hamartoma tumor syndrome)
●Risks – 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 [19]. Carriers have elevated risks for breast, endometrial, and thyroid cancer, particularly follicular cancer [14].
In a prospective study of almost 3400 patients meeting relaxed International Cowden Consortium PHTS criteria, including 368 individuals with a pathogenic variant, the estimated lifetime risk of developing breast cancer was 85 percent [20]. Most cancers are diagnosed premenopausally between the ages of 38 and 46 years [21], and in one study, 50 percent were impacted by age 50 [20].
It is estimated that up to 67 percent of women with a PTEN pathogenic variant also have an increased risk of benign breast changes (eg, intraductal papillomatosis, adenosis, lobular atrophy, and fibroadenomas). However, benign breast findings are not included in the National Comprehensive Cancer Network diagnostic criteria [14].
●Management – Women with PHTS are typically offered RRM, although some may opt instead for early breast cancer screening supplemented with MRI. Further discussion is found elsewhere. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cancer surveillance'.)
Although pathogenic variants in PTEN do not appear to confer a significantly increased risk for ovarian cancer, we discuss the potential risks and benefits of rrBSO with carriers who have a family history of ovarian cancer [14].
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)
●Risks – 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) [22]. It is associated with germline pathogenic variants in the cadherin 1 gene (CDH1) [23,24]. Germline CDH1 mutations are also associated with development of lobular breast cancer in women, with a cumulative lifetime risk estimated to be as high as 50 to 60 percent [22-26].
CDH1 pathogenic variants can cosegregate with invasive lobular breast cancer in the absence of diffuse gastric cancer, suggesting that gastric cancer is not an obligatory hallmark of families with CDH1 mutations [27]. Most CDH1 mutation carriers develop cancer before age 40 [22]. Identification of high-risk families and management of individuals who test positive for CDH1 are described separately. (See "Hereditary diffuse gastric cancer".)
CDH1 pathogenic variants have been identified in up to 50 percent of affected kindreds who meet the clinical criteria for HDGC. However, with increased testing by multigene panels, several individuals with pathogenic variants in CDH1 have been identified who do not meet diagnostic testing criteria for HDGC [28].
●Management – The evidence is insufficient to uniformly recommend RRM, although for those with a concerning family history (>20 percent risk of breast cancer by a model), it is reasonable to consider this option. For those with pathogenic variants in CDH1, we typically initiate annual mammography with tomography and annual breast MRI, starting at age 30 years. Use of tomography is preferred in this population to increase cancer detection rates relative to mammography alone. (See "Breast imaging for cancer screening: Mammography and ultrasonography", section on 'Digital breast tomosynthesis (DBT)'.)
Although pathogenic variants in CDH1 do not appear to confer a significantly increased risk for ovarian cancer, we discuss the potential risks and benefits of rrBSO with carriers who have a family history of ovarian cancer. (See "Hereditary diffuse gastric cancer", section on 'Surveillance for breast cancer'.)
Management of risks of gastric cancer is discussed elsewhere. (See "Hereditary diffuse gastric cancer", section on 'Management of CDH1 variant carriers'.)
MSH1, 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) [5,29,30]. The primary cancers associated with Lynch syndrome involve the colon, endometrium, ovaries, and stomach. Some, but not all, studies have suggested that there is an increased risk of female breast cancer in mutation carriers of MMR genes [29,31,32].
Pathogenic variants in MSH2 and MLH1 occur most commonly and confer lifetime risks of colon cancer of 52 to 82 percent, endometrial cancer of 25 to 60 percent, and ovarian cancer of 11 to 24 percent [33]. In a review of 21 studies, 13 found no statistical increase in breast cancer risk, and 8 reported an increased risk ranging from 2- to 18-fold compared with the general population [34]. Two large subsequent cohort studies have found no statistically significant risk of breast cancer with the MMR genes [35,36]. Given the inconsistency in data about breast cancer risk in Lynch syndrome, forthcoming prospective data are important.
Multigene panel testing is identifying individuals with pathogenic variants in Lynch syndrome genes who do not meet diagnostic criteria for Lynch syndrome. For example, in a study of 528 patients with Lynch syndrome pathogenic variants, only 22 percent met national testing criteria for BRCA1/2 and 5 percent met neither BRCA1/2 nor Lynch syndrome testing criteria [37]. Among patients who met BRCA1/2 testing criteria, pathogenic variants in MSH6 and PMS2 were more common than the other MMR genes.
●Management – rrBSO and hysterectomy for ovarian and endometrial cancer risk reduction is typically suggested for women with Lynch syndrome, upon completion of childbearing. The evidence is insufficient to uniformly recommend RRM, although for those with a concerning family history (>20 percent risk of breast cancer by a model), it is reasonable to proceed with this option, according to patient preference [38]. Further 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'.)
PALB2 — Partner and localizer of BRCA2 (PALB2) is a breast cancer susceptibility gene that encodes a BRCA2-interacting protein [39,40]. The BRCA2-PALB2 interaction is crucial for key BRCA2 DNA damage response functions as well as tumor suppression activity [41,42]. (See "Gene test interpretation: PALB2".)
●Risks – The cumulative lifetime breast cancer risk to age 80 for all female carriers is approximately 44 percent, whereas the cumulative risk to age 49 is approximately 14 percent [43]. 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 [35,36]; 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 [36].
In comparison with the general population, the relative risk of breast cancer for a woman with a PALB2 pathogenic variant based upon her age is [44]:
•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 moderate- to high-risk gene associated with hereditary breast cancer [43-46]. Breast cancer risk associated with a PALB2 pathogenic variant appears to be influenced by a family history of breast cancer and other as yet unidentified environmental and lifestyle factors [44,47]. In a study of 362 members of 154 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 [44]:
•No family history of breast cancer – 33 percent (95% CI 25-44)
•Two or more family members with breast cancer – 58 percent (95% CI 50-66)
Although rare, monoallelic deleterious PALB2 pathogenic variants are present in a small but substantial proportion of patients with breast cancer [44,48], including approximately 1 percent of patients with breast cancer and approximately 1 percent of patients with triple-negative breast cancer [49,50]. 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 [51].
Several studies have shown that PALB2 pathogenic variants are associated with a low absolute risk of ovarian cancer [4,47,52]. They also appear to be associated with an increased risk of pancreatic cancer, although the absolute risk is unclear [47,53,54]. In addition, PALB2 pathogenic variants may also be associated with increased risks for breast cancer in men, prostate cancer, and medulloblastoma, although these risks are not confirmed and are also difficult to quantify [4,47,55-58].
Biallelic mutations in the PALB2 gene, also known as FANCN, cause Fanconi anemia [59]. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)
●Management – For women with pathogenic variants in PALB2, we typically initiate annual mammography with tomography and annual breast MRI, starting at age 30 years. RRM may be a strong consideration for some patients, especially for those with a concerning family history or other risk factors (eg, atypia or a breast cancer diagnosis) [14]. Although pathogenic variants in PALB2 do not appear to confer a significantly increased risk for ovarian cancer [40], we offer rrBSO to carriers who have a family history of ovarian cancer. For most women, such surgery can occur after menopause, unless there is a family history of premenopausal ovarian cancer.
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.
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'.)
MODERATE-PENETRANCE GENES
General considerations
●Risks – In addition to well-described familial syndromes and high-penetrance genes associated with an increased risk of breast and/or ovarian cancer, other gene variants appear to at least moderately increase the risk of these cancers. Women who have pathogenic variants in neurofibromatosis type 1 (NF1), ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2), BRCA1-associated RING domain 1 (BARD1), or nibrin (NBN) have a moderate lifetime risk of breast cancer, and those with mutations in BRCA-interacting protein 1 (BRIP1), 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 women with pathogenic variants in moderate to high penetrance are useful for counseling purposes (table 1) [43].
Several large case-control studies have described the associations between a number of possible cancer susceptibility genes and the risk of breast cancer [5,49]. 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 women from 25 countries, and evaluated 34 genes [35]; separately, 28 genes were evaluated in 64,000 women from the United States [36]. Aside from BRCA1 and BRCA2, variants in PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 were associated with breast cancer risk in both studies. 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 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 [60].
●Considerations regarding surveillance and risk management – Decisions about chemoprevention and risk-reducing mastectomy (RRM) and/or salpingo-oophorectomy should be highly individualized based upon the woman'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 magnetic resonance imaging (MRI) is recommended, and whether mastectomy is offered. For women 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 [61]. Some such women 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 women 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.
Greater association with ER-positive breast cancer
CHEK2 — The checkpoint kinase 2 (CHEK2) gene is associated with the DNA damage repair response Fanconi anemia (FA)-BRCA1/2 pathway [62,63]. (See "Gene test interpretation: CHEK2".)
●Risks – It is critical to review the test report carefully (algorithm 1). Risk information and associated management recommendations for variants in the CHEK2 gene are dependent on the specific variant identified. Although protein truncating or frameshift variants appear to heighten the risk for breast cancer, missense variants may confer lesser risks.
In two large cohort studies, there was a greater association for estrogen receptor (ER)-positive breast cancer than for ER-negative breast cancer, among CHEK2 carriers [35,36]; for example, the odds ratio (OR) was approximately 2.6 for ER-positive disease in carriers relative to the noncarriers (versus approximately 1.4 to 1.6 for ER-negative disease). (See 'Moderate-penetrance genes' above.)
Several CHEK2 variants have been identified [64], including one polymorphism (1100delC) that appears to be associated with a low- to moderate-penetrance breast cancer susceptibility allele [64-71].
•The 1100delC protein-truncating variant is associated with a two- to threefold increased risk of breast cancer, predominantly among White Americans and Europeans of Northern or Eastern European descent [65,72-77]. One study suggested that of those with this mutation, there is a 37 percent (95% CI 26-56 percent) risk of breast cancer by age 70 years [78]. Age-specific estimated risks have been published [43]. The lifetime cumulative risk of breast cancer to age 80 in women with this variant is approximately 32 percent, whereas the cumulative risk to age 49 is approximately 6 percent.
•Cancer risks associated with most missense variants in CHEK2 are unclear; however, the breast cancer risk associated with some variants appears to be lower. For example, I157T is associated with only a modest increase in breast cancer risk (OR 1.58, 95% CI 1.42-1.75) [79]. 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 [43].
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 [74]:
•Be younger at the time of diagnosis (mean age, 50 versus 54; p <0.001)
•Have a family history of breast cancer (13 versus 10 percent; p <0.001)
•Develop ER-positive breast cancers (63 versus 57 percent; p <0.001)
•Develop a second primary breast cancer (hazard ratio [HR] 3.52, 95% CI 2.35-5.27)
The risks for other CHEK2-associated cancers are not well defined. However, the 1100delC variant appears to be associated with an increased risk for colorectal cancer, particularly in the setting of a family history of colon cancer [80]. For example, the cumulative risk of colorectal cancer for 1100delC carriers to age 49 is estimated to be 0.6 percent, with a cumulative lifetime risk to age 85 for all carriers of approximately 12 percent [81]. This compares with a lifetime risk in the general population of approximately 6 percent.
Studies have also found that CHEK2 carriers have increased risks for male breast cancer [82], as well as stomach, prostate, kidney, leukemia, plasma cell neoplasms, and thyroid cancer and sarcoma [65,83,84]. At present, there is no strong evidence that CHEK2 mutations confer an increased risk of ovarian cancer given how infrequently they are identified in women with ovarian cancer [4,85].
●Management – For those with pathogenic variants in CHEK2, we typically initiate annual mammography with tomography and annual MRI, starting at age 40 years, given evidence of moderately increased lifetime risk of breast cancer. The evidence is insufficient to uniformly recommend RRM, although for those with a concerning family history or other risk factors (eg, atypia or a breast cancer diagnosis), it may be reasonable for carriers to consider this option [14].
For select women at risk for breast cancer, chemoprevention with endocrine therapy may be an appropriate option. In particular, women with CHEK2 mutations are more likely to develop ER-positive breast cancers and thus may be good candidates for chemoprevention with tamoxifen or related agents [86], although 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.
Patients with CHEK2 mutations require screening colonoscopy rather than other screening modalities for colon cancer. For those without a first-degree relative with colorectal cancer, colonoscopy is performed every five years, beginning at age 40; for those with a first-degree relative with colorectal cancer, colonoscopy is performed every five years beginning either at age 40, or ten years prior to the age of the first-degree relative's age at colorectal cancer diagnosis [87].
Shared decision making between male CHEK2 carriers and their clinicians regarding prostate cancer screening should begin at age 40 years.
ATM — Heterozygotes for a single pathogenic AT 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 30 percent (and 6 percent to age 49) [43,88-92]. 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 [35,36]; 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 [89,90]. The risk of second primary breast cancer is not clear [93]. Although it is also possible that there is an increased risk of ovarian cancer based on results of a case-control study [5], these data need to be confirmed.
It is estimated that approximately 3 percent of White people in the United States are ATM heterozygotes [94]. 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) [88]. Relatives of individuals with ataxia-telangiectasia (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 [84,95]. There may also be higher risks of ovarian cancer and gastric cancer, but more data are needed to confirm these findings [5,84]. 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 AT variant are also at possibly higher risk of coronary artery disease [96].
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 and annual MRI, starting at age 40 years, given evidence of moderately increased lifetime risk of breast cancer [14]. 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 [96]. 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 [14]. Breast surveillance recommendations may be modified based on genotype and family history [96].
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 [97]. 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 [98]. 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 [15,96].
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.
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'.)
Greater association with ER-negative breast cancer
BARD1 — BRCA1-associated RING domain 1 (BARD1) is involved in the FA-BRCA1/2 pathway. (See 'CHEK2' above.)
●Risks – BARD1 mutations may be cancer-risk alleles and predispose to an increased risk of breast cancer in women, and possibly ovarian cancer as well [4,99,100], on the order of 15 to 40 percent [33]. In two large cohort studies, there was a greater association for estrogen receptor (ER)-negative breast cancer than for ER-positive breast cancer among BARD1 carriers [35,36]; for example, in one study, the ORs relative to noncarriers were 2.5 for ER-negative cancers and 0.9 for ER-positive cancers [36].
●Management – For those with pathogenic variants in BARD1, we do not perform early mammography or breast MRI, unless their family history places them at increased risk. Although the presence of a BARD1 pathogenic variant is not by itself an indication for RRM, women with personal and family history risk factors may elect for this. (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.
●Risks – RAD51C and RAD51D mutations are rare and confer an increased risk of ovarian cancer, as well as an increase in risk for triple-negative breast cancers [14,33,35,36,101-109]. Ovarian cancer risks and management are discussed below. (See 'RAD51 paralogs' below.)
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 [35,36]; for example, in one study, the ORs relative to noncarriers were 9.2 for ER-negative cancers and 3.1 for ER-positive cancers [36].
●Management – For those with pathogenic variants in RAD51 paralogs, we do not perform early mammography or breast MRI, unless their family history places them at increased risk.
Association with ER-positive and ER-negative breast cancer
NF1 — Pathogenic variants in neurofibromatosis type 1 (NF1) give rise to neurofibromatosis 1 [110,111], 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 [112-114]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis" and "Neurofibromatosis type 1 (NF1): Management and prognosis".)
●Risks – A heightened risk for breast cancer has been observed among individuals with NF1 pathogenic variants, particularly younger women. For example, in a Finnish registry study of 1400 patients with NF1 pathogenic variants, the standardized incidence ratio of breast cancer for those with NF1 compared with those without NF1 was 11.1 (95% CI 5.6-19.5) for women <40 years [115]. Similarly, in a registry study of all inpatient admissions in England, 3700 women with NF1 were identified, among whom the relative risk (RR) of breast cancer compared with the general population was higher, especially in younger women (RR for women age 30 to 39 years, 6.5, 95% CI 2.6-13.5; age 40 to 49 years, RR 4.4, 95% CI 2.5-7.0; age 50 to 59 years, RR 2.6, 95% CI 1.5-4.2; age 60 to 69 years, RR 1.9, 95% CI 1.0-3.3; and age 70 to 79 years, RR 0.8, 95% CI 0.2-2.2) [116].
●Management – For those with pathogenic variants in NF1, we typically initiate annual mammography with tomography and annual breast MRI, starting at age 30 years, given evidence of increased risk observed in young women with pathogenic variants in NF1. Such women often consider prophylactic RRM, depending on personal and family history risk factors.
Management of risks for other cancers, including malignant peripheral nerve sheath tumors and gastrointestinal stromal tumors, is discussed elsewhere. (See "Neurofibromatosis type 1 (NF1): Management and prognosis".)
Associated with ovarian cancer
RAD51 paralogs — RAD51 paralog C (RAD51C) and RAD51 paralog D (RAD51D) mutations are rare and confer an increased risk of ovarian cancer, as well as a potential increase in risk for breast cancer (particularly triple-negative breast cancers) [14,35,36,101-109]. Breast cancer risks and management are discussed above. (See 'RAD51 paralogs' above.)
RAD51C mutations may occur in 1 percent of unselected women with ovarian cancer and are associated with an ovarian cancer risk of approximately 9 to 11 percent [107,109]. In a case-control study of 3400 women with epithelial ovarian cancer and 2700 controls, both RAD51 paralogs were associated with a risk of ovarian cancer (RAD51C OR 5.2, 95% CI 1.1-24; RAD51D OR 12.0, 95% CI 1.5-90.0) [102].
The estimated cumulative ovarian cancer risk for RAD51C carriers is approximately 1 percent by age 49, and the risk to age 80 is approximately 6 percent [43]. In RAD51D carriers, the estimated cumulative risk of ovarian cancer is approximately 1 percent by age 49 and is approximately 14 percent to age 80 [43].
●Management – For those with pathogenic variants in RAD51C or RAD51D, we recommend rrBSO beginning when the patient is 45 to 50 years, per National Comprehensive Cancer Network (NCCN) guidelines [14]. We inform women that, although there are no data in these gene carriers, use of oral contraceptives may reduce the risk of ovarian cancer, as observed in women with pathogenic variants in BRCA1/2 [117].
BRIP1 — BRCA-interacting protein 1 (BRIP1) is a DNA repair gene that interacts with BRCA1. Biallelic germline mutations of this gene result in FA complementation groups [118].
●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 [119-124]. For example, in a case-control study of 3200 women with ovarian cancer, 3400 healthy controls, and 2000 unaffected women at high risk for ovarian cancer, BRIP1 was associated with an increased risk of ovarian cancer (RR 11.22, 95% CI 3.22-34.10) [123]. The cumulative lifetime risk of ovarian cancer to age 80 ranges between approximately 4 and 13 percent depending on the study methodology [43].
●Management – For those with pathogenic variants in BRIP1, we recommend rrBSO beginning when the patient is 45 to 50 years, per NCCN guidelines [14]. We inform women that, although there are no data in these gene carriers, use of oral contraceptives may reduce the risk of ovarian cancer, as observed in women with pathogenic variants in BRCA1/2 [117].
Given that breast cancer risks are not well defined, no guidelines exist about how to manage breast cancer risks in women with pathogenic variants in newly identified genes, including BRIP1. In such cases, breast cancer risk may still be assessed based on personal and family history. Such women may wish to discuss the option of RRM, particularly if they have a strong family history.
GENES PREVIOUSLY THOUGHT TO BE IMPLICATED IN BREAST CANCER
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 [125]. While some prior studies have suggested that MUTYH heterozygotes have an increased risk of breast cancer [126-128], the more recent and definitive large population-based case-control studies found no increased risk for breast cancer [35,36], although one has suggested an increased risk of kidney cancer [84]. We do not perform early mammography or breast magnetic resonance imaging (MRI), unless their family history places them at increased risk.
Homozygous and biallelic carriers have an increased risk of colorectal polyposis and cancer [129-132]. Women with MSH mutations require screening colonoscopy. (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 [133-140]. The most common pathogenic variant in patients of Eastern European descent is hypomorphic, leading to a partially functional protein [141]. Other mutations are more common in different populations [142]. 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 [143,144], the more recent and definitive large population-based case-control studies found no increased risk for breast cancer [35,36]. Other studies also failed to demonstrate an association between pathogenic variants in NBN and breast cancer [49,145]. 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 women who test positive for a gene associated with hereditary breast and/or ovarian cancers carry a pathogenic variant in one of two susceptibility genes, breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2). However, pathogenic variants in partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2), and ataxia-telangiectasia mutated (ATM) together comprise a substantial proportion of cases, particularly for individuals with breast cancer. Much less commonly, breast or ovarian cancer is due to other 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 (PTEN) genes, respectively. (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.)
•Cancer risk management in patients with Li-Fraumeni syndrome, Peutz-Jeghers syndrome, PTEN hamartoma syndrome, hereditary diffuse gastric cancer, and Lynch syndrome are discussed elsewhere. Risk reduction strategies and/or early breast cancer screening and supplemental screening with breast magnetic resonance imaging (MRI) may be appropriate in some of these syndromes. (See "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 "Hereditary diffuse gastric cancer", section on 'Surveillance for breast cancer'.)
•For women with pathogenic variants in PALB2, we offer annual mammography with tomography and annual bilateral breast MRI starting at age 30 years. Pathogenic variants in PALB2 are associated with a heightened risk for estrogen receptor (ER)-negative breast cancers.
●Moderate-penetrance genes – Pathogenic variants in less well-characterized 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.)
•Women who have pathogenic variants in the genes CHEK2 and 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.
For these carriers, we recommend the following approach, consistent with recommendations from the National Comprehensive Cancer Network (see 'Moderate-penetrance genes' above):
-For women with pathogenic variants in cadherin 1 (CDH1) or neurofibromatosis type 1 (NF1), we offer annual mammography with tomography and annual bilateral breast MRI starting at age 30 years.
-For those with pathogenic variants in ATM or CHEK2, we offer annual mammography with tomography and annual bilateral breast MRI starting at age 40 years.
-For women with any of these pathogenic variants, the evidence is insufficient to uniformly recommend risk-reducing mastectomy, although for those with a concerning family history, it is reasonable to offer this option.
•Those with pathogenic variants in BRCA-interacting protein 1 (BRIP1) and the RAD51 paralogs (RAD51C and RAD51D) have a moderate lifetime risk for ovarian cancer. We do not routinely screen for ovarian cancer. However, for those with pathogenic variants in BRIP1, RAD51C, or RAD51D, we suggest risk-reducing salpingo-oophorectomy beginning when the patient is 45 to 50 years, given evidence for increased ovarian cancer risks (Grade 2C). However, data in this area are limited. (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.
