by Dr. George Gericke, Clinical Geneticist & Sarah Walters, Genetic Counsellor
PATHCHAT Edition No. 10
Please contact your local Ampath pathologist for more information.
Understanding BRCA1 and BRCA2 Mutations
🔹 Key Facts:
- BRCA1 and BRCA2 mutations account for:
- 5% of all breast cancer cases.
- 10–15% of all ovarian cancer cases.
- Women with BRCA1/2 mutations have:
- 50–85% lifetime risk of developing breast cancer.
- 15–40% lifetime risk of developing ovarian cancer.
- Higher risk of a second breast cancer diagnosis.
🔹 Types of BRCA Mutations:
- Over 1,000 mutations have been identified in BRCA1 and BRCA2.
- Some mutations are high-risk, while others are benign genetic variations.
- Cancer risk depends on the specific mutation and other individual factors.
🔹 BRCA Mutations in Men:
- BRCA1 mutation carriers may have an increased risk of breast and prostate cancer.
- BRCA2 mutation carriers have:
- >10% lifetime risk of developing breast cancer.
- 5–7 times higher risk of developing prostate cancer.
- More aggressive prostate cancer progression.
- Men aged 40–69 with a family history of prostate, breast, or ovarian cancer should:
- Undergo annual PSA testing.
- Consider BRCA1/2 testing if PSA >3 ng/mL.
- Consider screening mammography for BRCA2 carriers.
Determining Risk & When to Refer for Genetic Testing
🔹 Step 1: Take a Three-Generation Family History
- Consider both paternal and maternal family history.
- Men may be non-penetrant gene carriers, making paternal history equally important.
🔹 Step 2: Test the Most Likely Carrier First
- To minimize non-informative negative test results, test the family member most likely to carry a mutation first.
🔹 Step 3: Store DNA for Future Testing
- Extracted DNA from a patient with advanced cancer (breast, ovarian, prostate) can help in assessing other family members' risks later.
🔹 Step 4: Consider BRCA Testing for Triple-Negative Breast Cancer
- Triple-negative breast cancer (ER-, PR-, HER2-) diagnosed before age 60 is an indication for BRCA testing, regardless of family history.
- Triple-negative breast cancer occurs 3× more frequently in women of African descent.
🔹 Step 5: Consider Population-Specific Testing
- Founder mutations are more common in certain populations, making targeted testing more cost-effective:
- Ashkenazi Jewish descent & Afrikaner populations – Founder mutations account for ~90% of BRCA mutations.
- Western Cape Coloured & Xhosa populations – A frequent founder mutation has been identified.
Considerations for BRCA Testing
🔹 BRCA Testing is NOT Diagnostic
- It determines lifetime cancer risk for mutation carriers but does not confirm cancer presence.
- Not all cases of familial breast cancer are due to BRCA mutations.
- Negative BRCA results do not rule out genetic susceptibility to cancer.
🔹 Implications for Breast Cancer Patients
- Genetic testing at diagnosis can inform surgical and treatment decisions.
- Patients with deleterious mutations may opt for risk-reducing surgery on the contralateral breast at the same time as therapeutic surgery.
🔹 Common Misconceptions
- BRCA testing does not simply return a “yes” or “no” answer about inherited cancer risk.
- The test cannot detect all genetic risk factors for breast cancer.
🔹 More Information on BRCA Testing:
- Visit Myriad Genetics for more details.
When to Refer for Genetic Risk Evaluation
🔹 Individuals with Breast Cancer and One or More of the Following:
- Early-onset breast cancer.
- Triple-negative breast cancer (ER-, PR-, HER2-).
- Two primary breast cancers in the same individual.
- Breast cancer + one or more of the following family history criteria:
- >1 close relative with breast cancer <50 years old.
- >1 close relative with ovarian/fallopian tube/primary peritoneal cancer.
- >2 close relatives with breast and/or pancreatic cancer.
- Breast cancer + additional cancers in the family (thyroid, sarcoma, endometrial, pancreatic, brain, leukemia, etc.).
- Ovarian, fallopian tube, or primary peritoneal cancer.
- Male breast cancer.
🔹 Individuals Without Cancer But With a Strong Family History:
- >2 breast cancer cases in the same family (maternal or paternal).
- >1 ovarian cancer case in the same family.
- First- or second-degree relative with breast cancer <45 years old.
- A known BRCA mutation in a family member.
Pre-Test & Post-Test Genetic Counselling
🔹 Pre-Test Genetic Counselling
A genetic counsellor can:
- Assess risk based on family history.
- Explain test limitations, costs, and turnaround times.
- Discuss multiple testing tiers and financial implications.
🔹 Testing Considerations
a) Testing Family Members & Hereditary Risk
- BRCA mutations can be inherited from either parent and passed to sons and daughters.
- Each child of a carrier has a 50% chance of inheriting the mutation.
- Homozygous BRCA2 mutations can lead to Fanconi anaemia (FANCD1).
b) Testing in Minors
- Guidelines recommend delaying genetic testing for adult-onset cancers until age 18.
- Cancer screening in BRCA carriers typically starts in the mid-20s.
c) When to Consider Full BRCA Sequencing
- Ashkenazi Jewish or Afrikaner individuals with mixed ancestry.
- Families with strong breast/ovarian cancer history.
d) Targeted Testing of Family Members
- If a known BRCA mutation is identified in a family, relatives can be tested only for that specific mutation → Less expensive than full sequencing.
🔹 Post-Test Genetic Counselling
- For BRCA-positive individuals:
- Explanation of inherited risk & clinical implications.
- Review of risk management options.
- For BRCA-negative individuals:
- 70% of negative results are inconclusive.
- Cancer risk may still be high if family history is strong.
- A negative test does not rule out other genetic risks.
Other Genes Linked to Hereditary Breast Cancer
🔹 Genes with High Breast Cancer Risk:
- BRCA1 (65–81% lifetime risk) – Linked to early-onset breast & ovarian cancer.
- BRCA2 (45–85% lifetime risk) – Also linked to pancreatic & male breast cancer.
- TP53 – Associated with Li-Fraumeni syndrome (sarcoma, brain tumours, adrenal cancer).
- PTEN – Linked to Cowden syndrome (thyroid, endometrial, and colorectal cancer).
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