Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited cancer predisposition syndrome characterized by a combination of tumors including sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline mutations in the tumor suppressor gene TP53 are associated with LFS. We present a family with LFS in which initially a novel germline TP53 intron 5 splice site mutation was found. A second germline TP53 mutation, the exon 7 Asn235Ser (704A→G) mutation, was detected in this family through pre-symptomatic DNA testing. This latter mutation has been reported repeatedly in the literature as a pathogenic mutation involved in LFS. We provide evidence for pathogenicity of the novel intron 5 splice site mutation, whereas this evidence is lacking for the exon 7 Asn235Ser (704A→G) mutation. Our findings emphasize the importance of performing additional tests in case of germline sequence variants with uncertain functional effects.

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Familial Cancer
Erasmus MC: University Medical Center Rotterdam

van Hest, L., Ruijs, M., Wagner, A., van der Meer, C., Verhoef, S., van 't Veer, L., & Meijers-Heijboer, H. (2007). Two TP53 germline mutations in a classical Li-Fraumeni syndrome family. Familial Cancer, 6(3), 311–316. doi:10.1007/s10689-006-9115-7