BRCA testing, explained from biology to result
BRCA1 and BRCA2 are tumour-suppressor genes; an inherited pathogenic variant in either raises lifetime breast and ovarian cancer risk well above the population baseline. This explainer walks through the biology, the real risk figures, founder variants, what a positive, negative or VUS result actually means, and who meets testing criteria. Educational only — not medical advice.
What BRCA1 and BRCA2 actually do
BRCA1 (chromosome 17q21) and BRCA2 (chromosome 13q13) encode proteins central to homologous-recombination repair of double-strand DNA breaks. When one inherited copy carries a loss-of-function (pathogenic) variant, cells rely on the remaining copy; loss or silencing of that second copy impairs accurate repair, allowing the mutations that drive tumour formation to accumulate. This is why a single inherited BRCA1/BRCA2 variant — autosomal-dominant in inheritance — substantially elevates cancer risk, while the cancer itself develops through later somatic events.
Most BRCA-related cancers are breast and ovarian, but pathogenic variants also raise risk of pancreatic and prostate cancer, and male breast cancer. Around 10% of breast cancers and a larger share of ovarian cancers are hereditary, with BRCA1/BRCA2 the most common single contributors.
Approximate lifetime cancer risk by genotype
Indicative lifetime risk to age ~70–80, drawn from prospective and case-series estimates (NCI BRCA fact sheet; Kuchenbaecker et al., JAMA 2017; JCO 2022). Ranges vary by study, age and family history — treat as orientation, not a personal prediction.
From swab to sequencer: how a BRCA test runs
A germline BRCA test reads the inherited sequence of <code>BRCA1</code> and <code>BRCA2</code> (often within a wider panel) from a non-tumour sample. The path from collection to report is broadly the same across clinical laboratories.
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1 · Collect the sample
Saliva (e.g.
OG-500, ~2 mL stabilised in lysis buffer), a buccal swab, or a blood draw provides germline DNA. Stabilised saliva is shelf-stable at room temperature for weeks, easing postal return. - 02
2 · Extract & quantify DNA
The lab purifies genomic DNA and checks yield and integrity. Adequate, intact DNA is needed before library preparation — low-input samples may be recollected.
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3 · Library prep & sequencing
Targeted next-generation sequencing covers all coding exons and splice sites of
BRCA1/BRCA2, typically at high depth (commonly >100× mean) so single-base variants are called confidently. - 04
4 · Detect large rearrangements
Some pathogenic changes are large deletions or duplications that short reads miss; labs add MLPA or read-depth CNV analysis to capture them.
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5 · Classify the variants
Each variant is interpreted against the ACMG/AMP five-tier framework using population, computational, functional and segregation evidence, then assigned a clinical category.
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6 · Report with counselling
Results are returned through a clinician or genetic counsellor, who places them in the context of personal and family history and discusses next steps.
What each result type means
BRCA reports use the ACMG/AMP 2015 five-tier system. The category — not the mere presence of a variant — drives clinical action.
| Result | ACMG tier | What it means | Typical implication |
|---|---|---|---|
| Positive | Pathogenic / Likely pathogenic | A variant known (or very likely) to disrupt BRCA1/BRCA2 function — e.g. 185delAG (c.68_69delAG) in BRCA1. | Elevated cancer risk; enhanced screening / risk-reduction options discussed; relatives may consider cascade testing. |
| VUS | Uncertain significance | A change whose effect on the protein is not yet established — insufficient evidence to call it harmful or harmless. | Not used to direct management; may be reclassified later as evidence accrues. Manage on family history, not the VUS. |
| Negative — true | Benign / Likely benign, or no variant | No disease-causing change detected in the genes tested. | Risk assessed from family history; a 'negative' does not erase risk if a known familial variant was not tested for. |
| Negative — uninformative | No known familial variant | Tested when no specific familial variant is known and none is found. | Residual risk remains; screening still guided by personal and family history. |
Table 1. ACMG/AMP variant categories as applied to germline BRCA1/BRCA2 reporting (Richards et al., 2015).
Glossary
A few terms that recur on BRCA reports.
- Pathogenic variant
- A change with strong evidence that it disrupts gene function and raises disease risk; the basis of a 'positive' result.
- VUS
- Variant of uncertain significance — a change with insufficient evidence to classify as benign or pathogenic. It should not, on its own, change clinical management.
- Founder variant
- A specific pathogenic variant common in a population descended from a shared ancestor — e.g.
185delAGand5382insCinBRCA1, and6174delTinBRCA2, recurrent in Ashkenazi Jewish populations. - Cascade testing
- Testing blood relatives for a known familial pathogenic variant, so carriers and non-carriers can be identified.
- Germline vs somatic
- Germline variants are inherited and present in every cell (what a BRCA test reads); somatic variants arise within a tumour and are tested separately for treatment decisions.
Why ancestry can change the testing approach
In populations with founder effects, a small number of recurrent variants account for most BRCA-related cancer risk. Among people of Ashkenazi Jewish descent, three founder variants — 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2 — together explain the large majority of BRCA1/BRCA2 pathogenic variants, with a combined carrier frequency on the order of 1 in 40. Targeted three-variant panels can be efficient there, but full-gene analysis remains the way to detect variants outside the founder set. Ancestry is one input a clinician weighs when choosing a testing strategy.
Common questions
Who meets criteria for BRCA testing?
NCCN guidelines (Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic) outline who to test — for example, breast cancer diagnosed at a young age, ovarian cancer at any age, certain triple-negative or male breast cancers, a known familial pathogenic variant, or a relevant personal/family history pattern. Recent versions broadened several thresholds. Criteria are detailed and change over time, so eligibility should be confirmed with a clinician or genetic counsellor rather than self-assessed.
Does a negative result mean I will not get cancer?
No. A negative BRCA result lowers the likelihood of an inherited BRCA cause but does not remove ordinary population risk, and it cannot rule out variants in other genes or a familial variant that was not specifically tested for. Screening is still guided by personal and family history.
What should I do about a VUS?
A variant of uncertain significance is not actionable on its own and should not drive surgery or intensive screening. Many VUS are later reclassified — often as benign — as evidence accumulates. Management is based on family history; ask your laboratory or counsellor about reclassification updates.
Is saliva as reliable as blood for germline BRCA testing?
For germline testing, properly collected and stabilised saliva (such as a ~2 mL OG-500 sample) generally yields high-quality genomic DNA suitable for sequencing, and is convenient for postal return. Blood remains a common clinical sample. The laboratory specifies which sample types its assay validates.
“A BRCA result is a probability statement about inherited risk, not a diagnosis — its value comes from being read alongside a person's history, by someone qualified to act on it.”
- [1]NCI 2024. National Cancer Institute. BRCA Gene Changes: Cancer Risk and Genetic Testing Fact Sheet.↗
- [2]JCO 2022. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants. Journal of Clinical Oncology.↗
- [3]NCCN v2.2024. NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024. JNCCN.↗
- [4]ACMG/AMP 2015. Richards S et al. Standards and guidelines for the interpretation of sequence variants. Genet Med.↗
- [5]Sci Rep 2020. Identifying Ashkenazi Jewish BRCA1/2 founder variants in individuals who do not self-report Jewish ancestry. Scientific Reports.↗
- [6]DNA Genotek. Oragene OG-500 DNA self-collection kit — technical specifications.↗
Understand the result before you act on it
Pair this explainer with our walk-through of report language and tiers, and always discuss personal decisions with a clinician or genetic counsellor.