Mosaicism in genetic tumour syndromes

Abstract Inherited pathogenic variants in a series of cancer-associated genes cause monogenic genetic tumour syndromes (GTS). Nevertheless, in a subset of tumour-predisposed individuals, such variants have not been inherited through the germline but arose early in (embryonic) development. In such “constitutional mosaics”, the degree of mosaicism across different tissues may affect the severity of disease phenotype. In this review, the focus lies on genetic mosaicism in selected common GTSs, its implications for the phenotype and patient care, as well as assessment of offspring transmission risks and technical aspects of constitutional mosaicism detection. Constitutional mosaicism has been detected in varying frequencies in different GTS, often exceeding 10 % of tumour-predisposed patients lacking pathogenic germline variants. Notably, constitutional mosaicism will be missed in many instances by low-coverage sequencing, including low-coverage exome and whole-genome sequencing. Thus, the present review emphasises the need for comprehensive mosaicism testing across various tissues, particularly in seemingly sporadic cases with otherwise typical features of a GTS to improve diagnostic accuracy and patient care in GTSs.