BRCA 1 and 2

Article Author:
Jesse Casaubon
Article Editor:
John-Paul Regan
3/13/2019 3:59:31 PM
PubMed Link:
BRCA 1 and 2


One in 8 women (12.5%) in the United States will develop breast cancer throughout their lifetime. Certain populations are at an increased risk of developing cancer due to genetic or hereditary predisposition. Breast cancer genes BRCA1 and BRCA2 are tumor suppressor genes whose mutations significantly increase the likelihood of developing particular types of epithelial malignancies, namely breast and ovarian cancer [1][2]. Genetic or hereditary factors, including BRCA 1 and 2 mutations, have been found to be responsible for between 5% to 10% of breast cancer cases overall [3]. Hereditary breast and ovarian cancer syndrome (HBOC) due to BRCA1 and BRCA2 gene mutation is inherited in an autosomal dominant fashion and makes up roughly half of the cancer cases related to inherited genetic risk [4].

The recognition of a genetic predisposition to cancer, knowledge of risk patterns in high-risk patients, and access to testing have all improved in recent years. Because of this, the ability to identify patients at risk, screen early, and prevent cancer have gained increased attention. The management of patients with a proven mutation of the BRCA1 and BRCA2 genes is individualized and can include increased surveillance, chemoprevention using tamoxifen, bilateral prophylactic oophorectomy and or bilateral prophylactic mastectomy [5].


The incidence of BRCA1 or BRCA2 mutations within the general population is infrequent and only found in 1 out of every 300 to 800 people [6]. Certain populations exhibit a higher likelihood of harboring genetic mutation than the general population. These include Ashkenazi Jewish patients, male patients who develop breast cancer, and patients younger than 30 years old who develop breast cancer. Founder mutations are particular mutations passed down between family members descendant from the same genetic lineage. The specific mutations found in members of Ashkenazi Jewish lineage include 185delAG and 5385insC in the BRCA1 genes and 6174delT in the BRCA2 gene at a rate of 1 in 40 [6].

While the risk for the development of breast cancer is the highest of the epithelial malignancies (between 40% to 80%), the likelihood of developing other cancers including ovarian, pancreatic, and prostate is also increased in patients with BRCA1 and BRCA2 mutations [7].


The normal risk for cancer development in the general population is 12.5% for female breast cancer, 0.1% for male breast cancer and 1% to 2% for ovarian cancer [2][4]. The incidence and associated risk for cancer development by age 70 for BRCA1 and BRCA2 mutations are listed below [8][9].

BRCA 1 Mutation

  • Responsible for approximately 35% of hereditary breast cancer
  • Increased risk of developing breast cancer by age 70 to 44% to 78%
  • Increased risk of developing ovarian cancer by age 70 to 18% to 54%
  • Increased risk of developing male breast cancer by age 70 to 0.22 to 2.8%

BRCA 2 Mutation     

  • Responsible for approximately 25% of hereditary breast cancer
  • Increased risk of developing breast cancer by age 70 to 31% to 56%
  • Increased risk of developing ovarian cancer by age 70 to 2.4% to 19%
  • Increased risk of developing male breast cancer by age 70 to 3.2% to 12%

History and Physical

The United States Preventive Service Task Force recommends that primary care physicians evaluate women who are candidates for hereditary cancer genetic testing by inquiring about family history of breast, ovarian, tubal or other cancers during annual examinations. If questioning reveals increased risk, referral to a certified genetic counselor (CGC) for possible testing is indicated (Grade B recommendations). Certified genetic counselors and breast surgeons may also aid in the decision regarding tests for BRCA alone, or for different genetic mutations related to other hereditary cancers [5].


American Society of Breast Surgeons emphasizes the importance of thorough patient history and uses the following criteria (similar to the NCCN guidelines for genetic risk evaluation).

Criteria for testing in patients with personal history of breast cancer and one or more of the following (from the NCCN and the American Society of Breast Surgeons Consensus Guideline on Hereditary Genetic Testing) [4][5]:

  1. Age of onset less than or equal to 50
  2. Triple negative tumor (ER-PR-HER2-) and age less than or equal to 60
  3. Ashkenazi Jewish heritage and breast cancer at any age
  4. Two or more primary breast cancer (either asynchronous, synchronous, bilateral, or multicentric)
  5. A first-degree relative with breast cancer diagnosed at age less than or equal to 50
  6. Two relatives on the same side of the family with breast cancer and/or pancreatic cancer
  7. Family or personal history of ovarian cancer, fallopian cancer, or primary peritoneal cancer
  8. Male breast cancer
  9. Known mutation carrier in the family

Testing patients who have not been diagnosed with cancer is typically reserved for situations when the affected family member or members cannot be tested. Criteria for testing patients without a personal history of breast cancer but with one or more of the following (from the NCCN and American Society of Breast Surgeons Consensus Guideline on Hereditary Genetic Testing) [5]

  1. First-degree or second-degree relative with age onset of breast cancer less than or equal to 45
  2. Ashkenazi Jewish heritage and family history of breast cancer at any age
  3. Two or more primary breast cancer (either asynchronous, synchronous, bilateral, or multicentric) in a single family member
  4. Two or more relatives on the same side of the family with breast and/or pancreatic cancer
  5. Family or personal history of ovarian, fallopian, or primary peritoneal cancer
  6. Male breast cancer
  7. Known mutation carrier in the family

In addition to the above criteria, likelihood or risk assessment models such as the BRCAPRO, BOADICEA, Penn II and IBIS can also be used to determine whether a patient is at an increased risk for carrying BRCA mutations and thus indicate the need for genetic testing or referral to a genetic counselor or breast surgeon . Though these models estimate the risk of developing breast cancer, no particular test or level of risk determines the need for or against BRCA testing.

Treatment / Management

Surveillance for Patients with BRCA1 and BRCA2 Mutations

An increased level of monitoring is mandatory for all patients with known BRCA mutations. The NCCN guidelines are widely accepted in the management of patients with BRCA mutation. The main goal of monitoring is early detection of malignancy and high-risk premalignant lesions. Early detection begins with breast awareness and self-breast examination beginning at age 18 and annual or semiannual clinical breast examination at age 25 (though neither of these has shown to benefit survival) [5].

Breast MRI increases sensitivity from approximately 33% to approximately 80% sensitivity in detection of malignancy in patients with familial or hereditary predisposition and has proven especially useful in this younger subset of patients. According to the NCCN guidelines, annual screening breast MRI with contrast is recommended annually from age 25 to 29 if available, or mammogram annually, if not. From age 30 to 75, annual mammogram and MRI of the breast with contrast is performed [5].

The treatment is personalized for each patient who is found to have a BRCA1 or BRCA2 mutation. This may include increased surveillance only, chemoprevention using tamoxifen or raloxifene, bilateral prophylactic salpingo-oophorectomy and or bilateral prophylactic mastectomy. Bilateral prophylactic mastectomy reduces the risk of developing breast cancer by 90% to 95% [10]. Referral to a breast surgeon for discussion regarding the option of risk-reducing mastectomy is indicated.


Patients with BRCA1 and BRCA2 mutation experience worse breast cancer specific survival when compared to BRCA-negative patients. BRCA1 carriers have worse overall survival than BRCA2 patients [11].

Pearls and Other Issues

A positive BRCA mutation indicates a higher likelihood of developing cancer but does not make or confirm the diagnosis of cancer. Subsequently, a negative BRCA test does not eliminate the risk of developing breast cancer from sporadic or other genetic causes.


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