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BRCA1 and BRCA2
BRCA1 and BRCA2 Clinician Guide
KNOWING WHAT TO LOOK FOR KNOWING WHERE TO LOOK AND KNOWING WHAT IT MEANS
BRCA1 and BRCA2
Breast cancer is the most common cancer in women, diagnosed in ~12%
of American women. While the majority of breast cancer occurs in women
with no family history of breast cancer, approximately 5-10% of all cases of
breast cancer are associated with a mutation in a single, highly penetrant
cancer predisposition gene. Mutations in the BRCA1 and BRCA2 genes are
the most common cause of hereditary breast and ovarian cancer (HBOC).
Women who carry a disease-causing mutation in one of these genes have
a significantly higher risk of developing breast and/or ovarian cancer. There
are also other types of cancer associated with a BRCA1 or BRCA2 mutation,
including fallopian tube, primary peritoneal, and endometrial (serous) cancer
in women, breast and prostate cancer in men as well as pancreatic cancer
in both men and women. Mutations in BRCA1/2 are thought to account for
approximately 15% of male breast cancers.1
Prevalence of BRCA1 and BRCA2 Mutations
Mutations in BRCA1 and BRCA2 are found in all ethnic and racial
backgrounds. Mutations occur in approximately 1 in 400 to 1 in 800
individuals in the general population in the United States, but are seen more
frequently in individuals of Ashkenazi Jewish descent.2,3,4 Approximately 1
in 40 individuals of Ashkenazi Jewish ancestry carry one of three diseasecausing founder mutations in BRCA1/2: c.68_69 delAG (also known
as 185delAG or 187delAG), c.5266 dupC (also known as 5382insC or
5385insC) in BRCA1, and c.5946 delT (also known as 6174delT) in BRCA2.
Genetics of BRCA1 and BRCA2
Mutations in both BRCA1 and BRCA2 are inherited in an autosomal
dominant manner. Therefore, an individual carrying a disease-causing
mutation in BRCA1 or BRCA2 has a 50% chance of transmitting the
mutation to a child, either male or female. Almost all individuals with a
mutation in BRCA1 or BRCA2 inherit it from a parent. Therefore, the siblings
of an individual with a mutation have a 50% chance of carrying the same
familial mutation. Extended family members are also at increased risk to test
positive for the familial BRCA1 or BRCA2 mutation. The exact risk depends
on the relationship to the patient.
CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2
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CLINICAL INDICATIONS FOR BRCA1/2 GENETIC TESTING
The following individuals have an increased risk for hereditary breast and
ovarian cancer and are appropriate candidates for BRCA1/2 testing:
1. An individual diagnosed with breast cancer, with one or more
of the following:
• Diagnosed ≤age 45
• Two primary breast cancers with the first diagnosed ≤age 50
• Diagnosed ≤age 50 with ≥1 close* relative with breast cancer
at any age or limited family history
• Diagnosed ≤age 60 with triple negative disease
• Diagnosed at any age with ≥1 close* relative with breast cancer diagnosed ≤age 50
• Diagnosed at any age and ≥2 close* relatives with breast cancer at any age
• Diagnosed at any age with ≥1 close* relative with epithelial ovarian, fallopian tube or primary peritoneal cancer
• Diagnosed at any age and ≥2 close* relatives with pancreatic cancer or aggressive prostate cancer at any age
• Diagnosed at any age with a close* male relative with breast
cancer diagnosed at any age
• Diagnosed at any age and of Ashkenazi Jewish ancestry, OR
2. Any woman diagnosed with epithelial ovarian, fallopian tube
or primary peritoneal cancer at any age, OR
3. Male with breast cancer at any age, OR
4.
An individual with a personal history of pancreatic cancer or
aggressive prostate cancer and ≥2 close* relatives with breast
and/or ovarian, fallopian tube or primary peritoneal cancer and/or pancreatic or aggressive prostate cancer, OR
5. An unaffected individual with a close* relative meeting the above criteria
In some cases, limited family history may not allow for evaluation of these criteria. Limited
family history is typically defined as <2 first- or second-degree female relatives living
beyond 45 years on the same side of the family.
*Close blood relatives include first, second and third-degree relatives on the same side of the family.
2
Genetic Test Results and What They Mean
There are three possible outcomes of genetic testing: positive, negative and
variant of unknown significance (VUS).
Positive Result
A positive result indicates that a disease-causing mutation was identified
in that individual and the risk for cancer is increased. Knowledge of a
positive result provides valuable information to the patient, physician and
family members. Knowledge of a patient’s genotype can assist in making
management and treatment decisions. Furthermore, testing of the patient’s
family members can allow for accurate predictions of cancer risks.
Negative Result
A negative result means that a disease-causing mutation was not identified
in the individual tested. A negative result can have different interpretations
based on the following scenarios:
True Negative: An individual who tests negative for a known familial mutation
is not a carrier of a known cancer-predisposing mutation that has been
identified in another family member. The risk for cancer in this individual is
generally not expected to be greater than the general population risk. While
general population screening is usually indicated, clinical assessment of the
complete family history of cancer and personal risk factors is important to
determine appropriate management.
Uninformative Negative: If testing was performed on an individual with a
cancer diagnosis, this means that we do not have an explanation for why
this individual developed cancer. Genetic counseling is recommended, as
additional testing may be considered based on the individual’s medical and
family history. If testing was performed on an individual without a personal
history of cancer and based only on family history, the risk for cancer may
remain increased as the exact cause of the cancer in the family remains
unknown. Testing of an affected family member may help clarify this
individual’s cancer risks.
Variant of Unknown Significance (VUS)
A variant of unknown significance (VUS) indicates that the pathogenicity
of the variant cannot be clearly established. To further clarify the clinical
CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2
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significance of this variant, testing of family members may be helpful. If
a relative with a related cancer is found to have the same variant, it may
provide evidence that the variant may be disease-causing. The greater the
number of affected family members who carry the VUS, the greater is the
likelihood that the VUS is pathogenic. With consistent linkage of the VUS
with family members with related cancers, in addition to other evidence, the
variant found may be reclassified as a family-specific mutation and predictive
genetic testing can be offered to extended family members. Conversely, a
VUS could be determined to be benign through this and other research.
GeneDx will review a patient’s detailed family history to determine if family
members are eligible for complementary targeted variant testing through our
Variant Testing Program.
BRCA1/2-Associated Cancer Risks
and Pathology
Mutations in BRCA1 and BRCA2 increase the lifetime risk for breast and
ovarian cancer significantly over the general population risk. In general,
the risk of breast and ovarian cancer is slightly higher for BRCA1 mutation
carriers than BRCA2 mutation carriers and usually the cancers occur earlier
for BRCA1 mutation carriers in comparison to BRCA2 mutation carriers.
Women with BRCA1 mutations have between 57-87% lifetime risk to
develop breast cancer and women with BRCA2 mutations have a 4184% lifetime risk to develop breast cancer.3,5,6,7 The lifetime risk to develop
ovarian cancer is between 24 and 54% for BRCA1 and 11 and 27% for
BRCA2 mutation carriers. 6,7,8,9 The chances to develop breast cancer
begin increasing when a woman is in her mid 20’s.9 The risk of ovarian
cancer begins to increase in the mid 30’s, but becomes most significant
in the 50’s and beyond. Additional cancers in women include fallopian
tube carcinoma, primary peritoneal carcinoma, and endometrial serous
carcinoma.10,11,12
The lifetime risk for breast cancer in male BRCA1/2 mutation carriers is
increased. Men with BRCA2 mutations have a 4-7% risk for male breast
cancer.1,14 The risk for BRCA1 mutation carriers is increased, although
not well defined. 1,14,15 The risk for other malignancies has been reported
in families with mutations in BRCA1 or BRCA2, including prostate cancer
4
BRCA1/2-Associated Lifetime Risks by Cancer Type
100
BRCA1*
57-87% 41-84%
BRCA2
Probability (%)
80
60
24-54%
40
20-34%
11-27%
20
5-7%
4-7%
0
Female
Breast
Male
Breast*
Ovarian
Pancreatic*
Prostate*
Cancer Type
*Individuals with BRCA1 mutations have increased risks for male breast, prostate,
and pancreatic cancers, however the exact risks are not well-defined.
in men as well as pancreatic cancer in both men and women. Men with
BRCA2 mutations have up to a 34% risk of prostate cancer16 and both
men and women with BRCA2 mutations have a 5-7% risk of pancreatic
cancer.17,18 Individuals with BRCA1 mutations have increased risks for
these cancers, although the exact risks are not well-defined. 1,15,19,20
The relative risk of prostate cancer has been shown to be greater in
BRCA1/2 carriers under the age of 65.1 Lastly, the risk to develop
melanoma skin cancer is increased in men and women with BRCA2
mutations.1,18
Women with BRCA1/2 mutations also have an increased risk for
contralateral breast cancer. This risk may depend on the age at which the
first breast cancer was diagnosed. Table 1 describes the risk of a second
primary breast cancer based on age of diagnosis of the first breast cancer.
The majority of BRCA1-related breast cancers are invasive ductal
carcinomas. These tumors are also more likely to be of higher histologic
grade. Triple negative breast cancer (estrogen receptor-negative,
progesterone receptor-negative, and lacking HER2/neu overexpression)
CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2
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Risk of second primary breast cancer
Age of Diagnosis of
First Breast Cancer
Within 10 years
Within 25 years
Under age 40
21-31%
63%
Between ages 40 and 50
11-13%
44-49%
After age 50
8-9%
17-20%
Table 1: Risk of second primary breast cancer based on age of diagnosis of first breast cancer in
BRCA1/2 positive women 13
is also more common in BRCA1 mutation carriers compared to patients with
sporadic breast cancer. BRCA2-related breast cancers are usually hormone
receptor-positive.21
Ovarian cancers related to BRCA1 or BRCA2 mutations are usually serous
adenocarcinomas and more likely to be high grade compared to ovarian
cancers in non-carriers.22,23 BRCA2-associated prostate cancer is more likely
to have a high histologic grade compared to sporadic tumors.24 High grade
tumors are often more responsive to chemotherapy, and do not necessarily
portend a worse prognosis with appropriate treatment.25,26
Management of BRCA1/2-positive Patients
There are a variety of management strategies available to patients
who test positive for a disease-causing mutation in BRCA1 or BRCA2.
Various guidelines outline available options and recommendations
for patients who have a positive BRCA1 or BRCA2 test result. These
options include increased screening, surgery and chemoprevention. The
guidelines below are examples of current recommendations as of 2014.
Please visit www.nccn.org for the most up-to-date recommendations,
including ages to begin surveillance and current recommended
screening frequencies.
Increased Screening:
For women, increased screening includes the following:
• Increased breast awareness including self breast exam
• Routine clinical breast exam
6
• Breast MRI and mammogram starting at an early age
•Consider transvaginal ultrasound of the ovaries and CA-125 blood
tests
•Consider full body skin exam
• Consider pancreatic cancer screening
For men, increased screening includes the following:
• Increased breast awareness including self breast exam
• Routine clinical breast exam
•Consider baseline mammogram with repeat imaging if gynecomastia
or parenchymal/glandular breast density is noted on baseline study
• Routine prostate cancer screening starting at an early age
• Consider full body skin exam
• Consider pancreatic cancer screening
Risk Reducing Surgery:
• Consider prophylactic mastectomy; mastectomy reduces the chance
of developing breast cancer by at least 90%.
• Salpingo-oopherectomy is recommended (as early as the 30s-40s)
once a woman has completed childbearing; this reduces the risk
of ovarian cancer by approximately 80% and, if performed prior to
natural menopause without hormone replacement, reduces the risk of
breast cancer by up to 50%.
Medication to Reduce Cancer Risk:
• Consider the use of breast cancer chemoprevention (such as
tamoxifen and raloxifene), which may reduce the risk of breast cancer.
• Consider the use of oral contraceptives, which may reduce the
risk of ovarian cancer by 45-50% in BRCA1 mutation carriers and
by 60% in BRCA2 mutation carriers. Risks and benefits should be
carefully considered, given conflicting evidence on the impact of oral
contraceptives on breast cancer risk.
Genetic Counseling
Pre-test counseling is recommended for individuals who are either
interested in understanding their risks and/or meet the clinical criteria and
are considering testing for BRCA1/2. If a disease-causing mutation has
CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2
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already been identified in a family member, testing of the specific mutation
is appropriate. If a disease-causing mutation has never been identified, an
affected family member with the highest likelihood for a positive result (early
onset disease, bilateral disease or multiple primaries) is ideally the best
candidate for initial testing within a family. If an affected family member is
not available for testing, testing of an unaffected family member with the
highest likelihood of testing positive for a mutation is recommended. Once
patients make the decision to undergo testing, post-test genetic counseling
is recommended to understand the implications of the results. Genetic
counseling services across the country can be found at: www.nsgc.org
More information about risk assessment and genetic counseling for hereditary
breast and ovarian cancer can be found at: www.nchpeg.org/hboc
Resources for Patients
Bright Pink: www.brightpink.org
FORCE: www.facingourrisk.org
NCI: www.cancer.gov
National Society of Genetic Counselors: www.nsgc.org
Sharsheret: www.sharsheret.org
Susan G. Komen: www.komen.org
References
1. Liede A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: A review of the
literature. J Clin Oncol. 2004 Feb;22(4):735-42
2. Ford D, et al. Risk of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet.
1994 Mar;343(8899):692-5
3. Claus EB, et al. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996 Jun;
77(11):2318-24
4. Whittemore AS, Gong G, and Itnyre J. Prevalence and contribution of BRCA1 mutations in breast
cancer and ovarian cancer: Results from three U.S. population-based case-control studies of ovarian
cancer. Am J Hum Genet. 1997 Mar; 60(3):496-504
5. Chen S and Parmigiani G. Meta-anlaysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007 Apr;
25(11):1329-33
6. Ford D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast
cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 Mar; #62(3):676-89
8
7. Risch HA, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances:
A kin-cohort study in Ontario. J Natl Cncer Inst. 2006 Dec; #98(23):1694-706
8. Antoniou A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2
mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am
J Hum Genet. 2003 May; 72(5):1117-30
9. King MC, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2.
Science. 2003 Oct; 302(5645):643-6
10.Levine DA, et al. Fallopian tube and primary peritoneal carcinomas associated with BRCA mutations. J
Clin Oncol. 2003 Nov; 21(22):4222-7
11.Biron-Shental T, et al. High incidence of BRCA1-2 germline mutations, previous breast cancer and
familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol.
2006 Dec; 32(10):1097-100)
12.Pennington KP, et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma.
Cancer. 2013 Jan; 119(2):332-8
13.Graeser MK, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin
Oncol. 2009 Dec; 27(35):5887-92
14.Tai YC et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst.
2007 Dec;99(23):1811-4
15.Brose MS et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation
program. J Natl Cancer Inst. 2002 Sep;94(18):1365-72
16.Thompson D, Easton D, Breast Cancer Linkage Consortium. Variation in cancer risks, by mutation
position, in BRCA2 mutation carriers. Am J Hum Genet. 2001 Feb;68(2):410-9
17.Ozcelik H, et al. Germline BRCA26174delT mutations in Ashkenazi Jewish pancreatic cancer patients.
Nat Genet. 1997 May; 16(1):17-8
18.The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst.
1999 Aug; 91(15):1310-6
19.Leongamornlert D et al. Germline BRCA1 mutations increase prostate cancer risk. Br J Cancer. 2012
May 8;106(10):1697-701
20.Thompson D, Easton DF, and the Breast Cancer Linkage Consortium. Cancer Incidence in BRCA1
mutation carriers. J Natl Cancer Inst. 2002 Sep;94(18):1358-65
21.van der Groep P, van der Wall E, and van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol.
2011 Apr; 34(2):71-88
22.Berchuck A, et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer
Res. 1998 Oct; 4(10):2433-7
23.Rubin SC, et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations
of BRCA1. N Eng J Med. 1996 Nov; 335(19):1413-6
24.Gallagher DJ, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer.
Clin Cancer Res. 2010 Apr; 16(7):2115-21
25.Bolton KL, et al. Association between BRCA1 and BRCA2 mutations and survival in women with
invasive epithelial ovarian cancer. JAMA. 2012 Jan; 307(4):382-90
26.Chetrit A, et al. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian
cancer: The national Israeli study of ovarian cancer. J Clin Oncol. 2008 Jan; 26(1):20-5
CLINICIAN GUIDE FOR INHERITED CANCERS: BRCA1/2
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