While further validation studies might be necessary to firmly establish the causal relationship between the POT1 p.P35L variant and multi-cancer phenotype, given the general relevance of POT1 in LFS/LFL and angiosarcoma patients, our study support the incorporation of POT1 testing into cancer gene panels for routine diagnostic purposes to enable early diagnosis, prevention and therapeutic intervention of individuals at risk. This evidence concerns the gene POT1 and cancer.