BRCA1 and BRCA2 mutations
Germline BRCA1 or BRCA2 mutation is an autosomal dominant tumor-suppressor defect that markedly raises lifetime risk of breast, ovarian, and other cancers. Management centers on risk assessment, genetic counseling and testing, and a structured program of enhanced screening, chemoprevention, and risk-reducing surgery timed to age and childbearing.
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What this article covers
- Overview
Germline tumor-suppressor mutation: breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), on chromosomes 17q12-21 and 13q12-13 respectively, are the two most…
- Epidemiology
Accounts for the most common hereditary breast cancer syndrome: BRCA1/2 mutations represent 5% to 10% of all breast cancer cases and are the most common familial breast cancer syndrome.
- Risk factors
Family history of a known deleterious BRCA1/2 mutation: the single strongest predictor; relatives of a known carrier warrant cascade testing.
- Pathophysiology
BRCA1/2 proteins normally execute homologous recombination repair at double-strand DNA breaks, using the intact sister chromatid as a template.
- Clinical features
Most carriers are identified before any cancer develops, through risk assessment: family or personal history meeting a validated risk-assessment tool or NCCN criteria is the presenting "feature," not a symptom.
- Differential diagnosis
Lynch syndrome (hereditary nonpolyposis colorectal cancer): mismatch repair gene mutation; presents with colorectal, endometrial, ovarian, or small bowel cancer clustering rather than predominant…
- Diagnosis
The diagnosis is established by germline genetic testing for pathogenic or likely pathogenic BRCA1/2 variants, performed after meeting NCCN testing criteria: breast cancer at or before age 45; breast…
- Management
Confirm the mutation and complete genetic counseling before any risk-reducing intervention, covering gene-specific risk, cascade testing, and reproductive implications.
- Complications
Development of invasive breast cancer, often earlier in onset with a higher rate of triple-negative or bilateral disease than sporadic cancer.
- Prognosis
Prophylactic bilateral mastectomy reduces breast cancer risk by greater than 90%, essentially neutralizing the hereditary excess risk.
- Prevention
Screen with a validated familial risk-assessment tool in every woman with a personal or family history of breast, ovarian, tubal, or peritoneal cancer, or a family history of a BRCA1/2 mutation; a…
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