What is the incidence of hereditary breast cancer associated with BRCA1 (Breast Cancer Gene 1) and BRCA2 (Breast Cancer Gene 2) gene mutations?

Incidence of Hereditary Breast Cancer with BRCA1 and BRCA2 Gene Mutations

Mutations in BRCA1 and BRCA2 genes account for 5-10% of all breast and ovarian cancer cases overall, with BRCA1 mutation carriers having a 65-80% lifetime risk of developing breast cancer and BRCA2 mutation carriers having a 45-85% lifetime risk. 1

Prevalence of BRCA Mutations

• Familial susceptibility accounts for approximately 25% of all breast cancer cases 1
• The prevalence of BRCA mutation carriers in the general population is estimated at between 1/800 and 1/1000 1
• BRCA1 and BRCA2 mutation frequencies in breast cancer patients unselected for family history or age at onset are generally low: <1-7% for BRCA1 and 1-3% for BRCA2 1
• Higher prevalence is associated with family history of breast or ovarian cancer, young age at onset, male breast cancer, or multiple tumors 1
• In the Ashkenazi Jewish population, the prevalence of specific BRCA mutations is significantly higher at approximately 1/50 1, 2

Lifetime Cancer Risks for BRCA Mutation Carriers

BRCA1 Mutation Carriers

• 65-80% lifetime risk of developing breast cancer 1
• 37-62% lifetime risk of developing ovarian cancer 1, 3
• Breast cancers tend to be of the basal-like phenotype, high histologic grade, and often triple-negative 1

BRCA2 Mutation Carriers

• 45-85% lifetime risk of developing breast cancer 1
• 11-23% lifetime risk of developing ovarian cancer 1, 3
• 5-10% lifetime risk of male breast cancer 1, 4
• BRCA2-related tumors more closely resemble sporadic tumors 1

Additional Cancer Risks in BRCA Mutation Carriers

• Increased risk of prostate cancer among BRCA carriers (5-25%) 1, 3
• Increased risk of pancreatic cancer (up to 2%) 1
• Increased risk of stomach and head and neck cancers 1

Population-Based Studies on BRCA Mutation Prevalence

• In young women with breast cancer (diagnosed before age 36), approximately 5.9% carry BRCA mutations (3.5% BRCA1, 2.4% BRCA2) 5
• In women diagnosed between ages 36-45, approximately 4.1% carry BRCA mutations (1.9% BRCA1, 2.2% BRCA2) 5
• 11% of patients with a first-degree relative who developed ovarian cancer or breast cancer by age 60 were mutation carriers 5
• 45% of patients with two or more affected first- or second-degree relatives were mutation carriers 5

Penetrance Estimates from Population Studies

• Some population-based studies suggest lower penetrance than high-risk family studies, with breast cancer penetrance by age 80 estimated at 48% for BRCA1 and 74% for BRCA2 6
• Ovarian cancer penetrance for BRCA1 and BRCA2 combined was estimated at 22% by age 80 in one population-based study 6
• BRCA1 and BRCA2 mutations account for approximately 17% of the familial risk of breast cancer 6

Clinical Implications and Testing Criteria

• Widely accepted criteria for genetic testing referral include: three or more breast and/or ovarian cancer cases with at least one diagnosed before age 50; two breast cancer cases diagnosed before age 40; male breast cancer with early-onset female breast cancer; and breast and ovarian cancer in the same patient 1
• Genetic testing should be performed after genetic counseling and informed consent 1
• Surveillance for BRCA carriers includes monthly self-examinations, clinical breast examinations once or twice a year, and yearly mammograms and MRI starting at age 25-30 1

Important Considerations

• Despite identification of multiple susceptibility genes, more than 70% of familial breast cancer cases remain unexplained genetically 7
• A negative BRCA1/2 test does not rule out hereditary breast cancer risk if family history remains suggestive 7
• The penetrance of BRCA mutations may vary by population, specific mutation, and environmental factors 8
• Mutations in other high-penetrance genes (TP53, PTEN, CDH1, STK11) also contribute to hereditary breast cancer but are rarer than BRCA1/2 mutations 1, 7