Tumour predisposition syndromes are typically diagnosed through blood-based genetic testing. However, pathogenic variants arising early in embryonic development may lead to mosaicism that escapes detection in blood. A recent JMG study shows that analysing multiple tissues can uncover these hidden variants and confirm the underlying genetic diagnosis. Multi-tissue analysis can therefore shorten diagnostic odysseys, improve cancer surveillance strategies, and clarify risk for affected individuals and their families. The findings highlight the clinical importance of considering mosaicism in hereditary cancer genetics. (https://doi.org/10.1136/jmg-2025-111224)