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Historically, it is estimated that 5-10% of cancer patients carry a causative genetic variant for a tumor predisposition syndrome. These conditions have high clinical relevance as they are actionable regarding risk-specific surveillance, predictive genetic testing, reproductive options, and - in some cases - risk reducing surgery or targeted therapy. Every individual is born with on average 0.5-1 exonic mosaic variants prevalent in single or multiple tissues. Depending on the tissues affected, mosaic conditions can abrogate the clinical phenotype of a tumor predisposition syndrome and can even go unrecognized, because it can be impossible or difficult to detect them with routine genetic testing in blood/leucocytes. On the other hand, it is estimated that at least 4% of presumed de novo variants are the result of low-level mosaicism (variant allele frequency <10%) in a parent, while around 7% are true mosaic variants with a higher variant allele frequency, which can sometimes be confused for heterozygous variants. Clonal hematopoiesis however can simulate a mosaic tumor predisposition in genetic diagnostics and has to be taken into account, especially for TP53 variants. Depending on the technique, variant allele frequencies of 2-3% can be detected for single nucleotide variants by next generation sequencing, copy number variants with variant allele frequencies of 5-30% can be detected by array-based technologies or MLPA. Mosaic tumor predisposition syndromes are more common than previously thought and may often remain undiagnosed. The clinical suspicion and diagnostic procedure for several cases with mosaic tumor predisposition syndromes are presented., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)