BRCA Testing in Pathology
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Direct answer
The same gene tells two stories — one in the germline, one in the tumour — and pathology adjudicates both. BRCA1 (17q21) and BRCA2 (13q12) encode homologous-recombination repair proteins; biallelic loss is tumorigenic, and heterozygous germline carriage defines hereditary breast-ovarian cancer syndrome. Tumour phenotype guides suspicion: BRCA1 drives triple-negative, high-grade, medullary-pattern carcinomas, while BRCA2 more often yields ER-positive high-grade tumours plus pancreatic, prostate and male breast risk. Testing proceeds by next-generation panels on blood (germline) or tumour-first strategies, and the therapeutic payoff is synthetic lethality — PARP inhibitors kill the BRCA-deficient cell that cannot also repair by PARP-mediated pathways.
What you must remember
- Genes and function: BRCA1 and BRCA2 are tumour suppressors in double-strand break repair by homologous recombination; loss produces the genomic scars (loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions) that HRD assays measure.
- Carrier risks (commonly quoted): BRCA1 — lifetime breast cancer roughly 55-72% and ovarian 39-44%; BRCA2 — breast 45-69%, ovarian 11-17%, plus pancreatic cancer, prostate cancer and melanoma; exact figures vary by study and population.
- Phenotype split: BRCA1 — triple-negative, Nottingham grade 3, medullary features, pushing borders, syncytia, dense TILs; BRCA2 — often ER-positive high grade; male breast cancer risk is notably higher with BRCA2.
- Testing triggers (evolving, guideline-based): breast cancer at a young age, all triple-negative disease (commonly offered for diagnosis at or under 60-65), any epithelial ovarian cancer, male breast cancer, pancreatic cancer, high-risk prostate cancer with family history, and strong family patterns.
- Founder mutations: Ashkenazi Jewish founders — 185delAG and 5382insC in BRCA1, 6174delT in BRCA2; no single equivalent pan-Indian founder has been established despite reported regional variant clusters.
- Testing strategy: multigene germline panels; a tumour-first (somatic) approach finds candidates but requires germline confirmation before calling hereditary; BRCA1 IHC loss is an imperfect surrogate.
- Therapeutics: platinum chemotherapy; PARP inhibitors olaparib and talazoparib in metastatic disease, and adjuvant olaparib in high-risk HER2-negative early disease with germline mutations.
A variant of uncertain significance
A 41-year-old with triple-negative breast cancer undergoes tumour sequencing; a BRCA1 missense variant of uncertain significance appears, plus a somatic BRCA1 truncating mutation. The rules that follow are examinable: a VUS must not guide surgery, risk-reducing mastectomy or relative testing — functional significance is unproven until reclassified, and laboratories maintain variant reclassification registries. The somatic truncation, however, is real within the tumour and supports platinum sensitivity; only germline testing of blood establishes whether it is hereditary. If the blood test finds the same truncation in every cell, the report becomes a family document — cascade testing for siblings and children, contralateral and ovarian risk discussions, and adjuvant olaparib eligibility per OlympiA-type criteria. This is the modern pathology consultation in miniature: sequence, classify, confirm in germline, and only then let the result change management.
Where students slip
The phenotype table is the viva staple: BRCA1 for triple-negative and ovarian, BRCA2 for male breast, pancreatic and prostate — reversed halves fail. Students also over-claim from IHC: absent BRCA1 staining suggests but does not prove deficiency, and retained staining does not exclude functional loss. The third slip is treating HRD scores as binary truth; they are computed composites with population-calibrated thresholds, meaningful mainly in ovarian and triple-negative contexts. Finally, a VUS must never be called a "positive" result to a patient — that single sentence is, in many vivas, the difference between a pass and a distinction in counselling stations.
Frequently asked questions
Which cancers are more strongly linked to BRCA2 than BRCA1?
Male breast cancer, pancreatic cancer, prostate cancer and melanoma; BRCA1 is the stronger driver of serous ovarian and triple-negative breast cancers.
What are the Ashkenazi founder mutations?
185delAG and 5382insC in BRCA1, and 6174delT in BRCA2 — founder variants carried at high frequency in that population.
What is homologous recombination deficiency testing?
A composite genomic-scar assay (loss of heterozygosity, telomeric allelic imbalance, large-scale transitions) identifying tumours functionally similar to BRCA-deficient ones, eligible for PARP inhibitors.
Why can a variant of uncertain significance not guide surgery?
Its effect on protein function is unproven; only pathogenic variants justify risk-reducing operations or cascade testing, pending laboratory reclassification.
What is the basis of PARP inhibitor efficacy?
Synthetic lethality: a cell lacking BRCA-mediated homologous recombination cannot survive PARP inhibition, while normal cells repair adequately.