01Core principlesThe concepts and mechanisms needed to understand the subject.
Hereditary breast cancer results when a constitutional pathogenic variant impairs a tumour-suppressor or DNA-repair pathway in every cell. Cancer develops after additional somatic events remove the remaining functional protection. BRCA1 and BRCA2-associated tumours illustrate defective homologous recombination, but they are not interchangeable: breast and ovarian risk, tumour phenotype and treatment implications differ by gene and individual. Many families with several cancers have no currently identifiable high-penetrance variant.
Genomic testing is a clinical process rather than a stand-alone blood request. The phenotype and pedigree select the appropriate commissioned panel, while counselling establishes what each class of result can and cannot answer. Testing an affected relative maximises information: if a familial pathogenic variant is found, unaffected adults can have targeted predictive testing. A variant of uncertain significance must not be used as though it proves inherited disease or justifies irreversible preventive surgery.
Key points
- Constitutional pathogenic variants are present throughout the body and can affect cancer risk, treatment and relatives; somatic variants are confined to tumour cells and are not automatically heritable.
- BRCA1 and BRCA2 encode proteins central to homologous-recombination DNA repair. PALB2 is another high-risk breast gene; TP53, PTEN, STK11 and CDH1 occur in broader cancer-predisposition syndromes.
- CHEK2, ATM, RAD51C and RAD51D can confer moderate or variant-specific breast risk. Management follows the exact gene, variant classification, family history, age and current NHS pathway.
- Clues include very young breast cancer, bilateral or multiple primary cancers, ovarian cancer, male breast cancer, related pancreatic or prostate cancers, selected tumour phenotypes and relevant ancestry.
- Test an affected relative first where possible because a pathogenic result identifies the familial target. A negative result in an unaffected person without an identified family variant may be uninformative.
- Pre-test counselling covers possible pathogenic, negative and uncertain results; consent includes family implications, data handling, psychological impact, surveillance, prevention and reproductive choices.
02Mechanisms and patternsImportant relationships and how to distinguish them.
Very young diagnosis, bilateral primaries or separate tumours in one person strengthen suspicion, particularly when combined with related cancers in relatives.
Breast, tubo-ovarian, pancreatic, male breast and some prostate cancers across either parental lineage can indicate homologous-recombination predisposition.
Sarcoma and childhood cancers suggest TP53; mucocutaneous findings or macrocephaly may suggest PTEN; diffuse gastric cancer raises CDH1 considerations.
Triple-negative breast cancer at a young age can trigger germline eligibility, but phenotype enriches probability and does not prove a constitutional variant.
03Interpreting evidenceInformation, measurements and their limitations.
Consider the information, its meaning and its limitations before deciding what follows.
- 01
Verified three-generation pedigree - Why
- Define which people and cancers make inherited predisposition plausible and identify the most informative living relative.
- Interpretation and limitations
- Record maternal and paternal lineages, exact primary sites, ages, bilateral disease and existing laboratory reports. Small families and adoption limit reassurance.
- 02
Constitutional multigene panel - Why
- Detect germline pathogenic variants in commissioned breast-cancer predisposition genes for eligible patients.
- Interpretation and limitations
- In NHS England, eligibility and gene content follow the current commissioned National Genomic Test Directory and local genomic pathway. Services in Scotland, Wales and Northern Ireland use their devolved arrangements. Interpretation must state pathogenicity and whether the assay addressed the family's clinical question. Verify eligibility against the current applicable clinical pathway.
- 03
Targeted predictive testing - Why
- Determine whether an unaffected adult carries a known familial pathogenic variant.
- Interpretation and limitations
- A true negative for the identified family variant can return gene-specific risk toward background modified by other factors; it is more informative than an untargeted negative.
- 04
Tumour genomic analysis - Why
- Identify somatic therapeutic biomarkers or a possible germline finding that needs confirmation in constitutional tissue.
- Interpretation and limitations
- A tumour-detected BRCA variant can be somatic. Use an appropriate blood or non-tumour sample with consent before labelling it inherited.
04Applied reasoningWorked examples connecting principles to decisions.
01Worked case: test the informative relativeResolve a familial BRCA questionIllustrative worked example: an unaffected 35-year-old asks about inherited risk after ovarian cancer in her mother and breast cancer at 39 in a living, previously untested maternal aunt.+
- 1Genetics verified the diagnoses and pedigree, obtained consent and arranged testing of the affected aunt first because her result offered the most informative route to a familial explanation.
- 2The aunt's constitutional laboratory report identified a pathogenic BRCA2 variant. With the aunt's agreement, the family received a written communication explaining the result and how relatives could access counselling.
- 3After counselling about possible results, psychological and reproductive implications, the unaffected patient chose targeted predictive testing for that exact familial variant rather than an unexplained broad panel.
- 4Her non-tumour sample tested positive for the familial BRCA2 variant. The clinician communicated the confirmed carrier result, checked understanding and arranged a gene-specific breast surveillance and risk-reduction consultation through the local genetics/breast service.
- 5At the subsequent appointment, the signed reports and referral were present, her surveillance plan had been agreed and she had received written contact details for relatives. She chose surveillance while considering preventive options, demonstrating an observed informed decision rather than an assumed obligation to undergo surgery.
02Tumour finding pathwayConfirm before calling it inheritedSequencing of a metastatic tumour reports a pathogenic BRCA2 variant, but no constitutional testing has been performed.+
- 1Check the specimen type, variant allele information and report wording; do not tell relatives they carry the variant.
- 2Refer for genetics review and consent for constitutional confirmation using non-tumour tissue under the current commissioned pathway.
- 3Use the tumour result for therapy only within the relevant oncology indication while germline status remains unresolved.
- 4If constitutional status is confirmed, address future primary-cancer risk, cascade testing and reproductive implications; if absent, document it as tumour-only.
03Uncertain variant pathwayProtect the patient from over-interpretationA multigene panel reports a variant of uncertain significance in CHEK2 and no pathogenic variant.+
- 1Explain that the evidence does not currently classify the variant as disease-causing or benign.
- 2Base surveillance and prevention on verified family history and calculated risk, not on treating the uncertain variant as positive.
- 3Do not offer predictive testing to relatives solely for the uncertain variant unless a genetics-led segregation study is specifically indicated.
- 4Ensure the laboratory or genetics service can update classification and the patient knows how material reinterpretation will be communicated.
05Checking understandingVerify the reasoning, revisit uncertainties and apply feedback.
- Keep the laboratory report, tested genes, assay limitations and variant classification attached to the correct person; verbal family summaries are not sufficient evidence.
- For carriers, track delivery of gene- and age-specific breast and other-organ surveillance through the specialist genetics plan rather than a generic annual check.
- Revisit reproductive goals, preventive surgery timing and psychological support as life circumstances change; a result does not require an immediate irreversible decision.
- Reassess variants only through the reporting laboratory or genetics service and update family advice when classification or the National Genomic Test Directory materially changes.
06Special situationsVariants, exceptions and circumstances that change the usual approach.
Germline and somatic differ
The same gene name may appear in tumour and blood reports, but only a confirmed constitutional variant establishes inherited risk to relatives.
Affected-first testing is efficient
Finding the causal variant in someone with the relevant cancer turns relatives’ testing into a precise familial-variant question.
Negative can be uninformative
When no familial variant is known, an unaffected person’s negative panel may leave substantial pedigree-based risk because an undetected cause remains possible.
Uncertain is not pathogenic
A variant of uncertain significance must not determine mastectomy, oophorectomy or predictive testing while causality remains unproven.
07Common pitfallsFrequent interpretation and management errors.
- 01
Telling a family that a tumour BRCA result is inherited before constitutional confirmation can cause inaccurate cascade testing and major anxiety.
- 02
Testing an unaffected relative first when an affected relative is available can produce a negative result that does not clarify the family.
- 03
Using one “hereditary breast cancer” management plan for BRCA1, BRCA2, TP53, PALB2 and moderate-risk genes ignores major gene-specific differences.
- 04
Interpreting a variant of uncertain significance as a positive result can drive unsupported surveillance and irreversible surgery.