The germline
A constitutional variant is generally present in many tissues and can be inherited by children. Blood or saliva are common specimens, but confirmation strategy changes with possible mosaicism, bone-marrow transplant and clonal haematopoiesis.
The somatic profile
Alterations arise in a tumour clone and can differ between primary and metastatic sites. Their purpose is to refine biology, prognosis or treatment sensitivity/resistance in a specific clinical situation.
Where the tests intersect
A pathogenic tumour finding in BRCA1/2, PALB2, MMR or TP53 can trigger separate germline confirmation. Allele fraction can inform a hypothesis but does not establish origin or replace separate germline testing and counselling.
Why paired tumour–normal can help
Paired analysis helps separate acquired from constitutional variants and reduce some misinterpretation, including clonal haematopoiesis. It also needs specific consent, a return-of-results policy and protection of family-relevant data.
What changes for a family
A confirmed pathogenic germline variant can change carrier surveillance and enable cascade testing for adult relatives. A relative’s negative result is informative only when the familial pathogenic variant is already known.