A tumour test asks about changes in cancer cells; a germline test asks about inherited or constitutional changes that may affect cancer risk. They can give different answers without either laboratory making a mistake. The sample, method, genes, reporting rules and clinical question all matter. A negative tumour result does not automatically remove an indication for germline testing, and a negative germline result does not rule out a treatment-relevant change acquired by the tumour.
This guide explains how to read discordant reports and prepare a genetics referral. The examples are fictional teaching cases, not treatment recommendations. For an actual result, decisions depend on the cancer type, personal and family history, the full laboratory reports and the clinical team.
Start with the question each test was designed to answer
| Question | Tumour profiling | Germline testing |
|---|---|---|
| What is sampled? | Tumour tissue, or sometimes circulating tumour DNA in blood. | Usually blood or saliva collected for constitutional DNA analysis. |
| What can it help explain? | Cancer biology and, in appropriate settings, treatment or trial options. | An inherited cancer predisposition and potential implications for relatives. |
| What is a common limitation? | A finding may be somatic or constitutional; a negative result may reflect the assay or specimen. | A negative finding does not exclude all hereditary risk or an acquired alteration in the tumour. |
| Can a blood sample settle the distinction? | No. A liquid biopsy is still a tumour-focused test. | The purpose and design of the assay, not just the sample container, define the test. |
Four common combinations of results
1. Germline positive, tumour negative
Imagine that a validated germline report identifies a pathogenic BRCA2 variant but a tumour report does not list it. Before concluding that the reports conflict, compare the exact variant and transcript. Was that region adequately covered? Could this tumour assay detect that variant class? Did low tumour content, filtering or reporting criteria affect the result? Is “not reported” being mistaken for “tested and absent”?
The germline finding still needs its own clinical interpretation. Whether the cancer has the biological features required for a particular therapy is a separate question. A multidisciplinary review can ask the laboratory for clarification without assuming that either test cancels the other.
2. Tumour positive, germline negative
A pathogenic alteration in a tumour may have arisen only in the cancer. A suitable negative germline test can support that interpretation, but first check that the germline assay actually examined the same alteration and relevant variant types. Low-level mosaicism and other technical issues may need specialist consideration when the history or findings are unusual.
Do not invite relatives for predictive testing solely on the basis of an unconfirmed tumour-only finding. Conversely, a somatic alteration may still matter for cancer treatment even when it is not inherited.
3. Both positive
Check that “positive” refers to the same finding. Constitutional risk, tumour behaviour and eligibility for treatment remain separate assessments. A pathogenic inherited variant does not, by itself, prove that every cancer in that person arose through that gene.
4. Both negative
Review the scope of both tests and the family history. “Nothing relevant was detected by these tests” is more accurate than “there is no genetic contribution.” New evidence, a different affected relative or a better-suited method may change the next step.
Why variant allele fraction is not a shortcut
A variant allele fraction near 50% is not proof that a tumour finding is inherited. Tumour purity, copy-number changes, loss of heterozygosity and biological mixtures can affect this number. The appropriate confirmatory test and clinical interpretation matter more than a single percentage. Also distinguish a tumour report’s oncogenicity or treatment tier from a germline pathogenicity classification: these systems address different questions.
When is specialist genetics input especially useful?
- A tumour finding could indicate a hereditary cancer syndrome.
- The personal or family history remains suspicious despite a negative test.
- Reports disagree about the same variant, or the assay’s coverage is unclear.
- A variant of uncertain significance is being used to justify major family or treatment decisions.
- Mosaicism, clonal haematopoiesis or an unusual sample source complicates interpretation.
- The patient wants treatment guidance but does not want inherited-risk information.
A referral that helps the team answer the question
Include the actual reports, not only the words “BRCA positive.” Record the cancer diagnosis and age at diagnosis, relevant pathology, family history, specimen type and collection date, laboratory and test name, exact variant nomenclature, classification, allele fraction if provided, and the decision that needs clarification. State whether constitutional testing or paired tumour–normal analysis has already been performed.
A useful referral question is: “Does this tumour finding warrant confirmatory germline testing, and would the answer change surveillance or counselling for this patient and relatives?” This is more actionable than “Please interpret genetics.”
If a patient declines inherited-risk information
Start by asking what the person wishes to know and what worries them. Explain that tumour testing intended to guide treatment can sometimes raise a possible inherited finding. Discuss the laboratory’s reporting approach, the limits of separating the two kinds of information, and available counselling. Document the person’s preferences and the agreed plan. Do not promise that a test can guarantee that no familial information will emerge.
The variant research tool can help organise terms and sources; it cannot replace interpretation of a clinical report. Use Find genetics care to prepare for a specialist consultation.