title: Two TP53 germline mutations in a classical Li-Fraumeni syndrome family.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Liselotte P
authors.initials: LP
authors.lastname: van Hest
authors.forename: Mariëlle W G
authors.initials: MW
authors.lastname: Ruijs
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.forename: Conny A
authors.initials: CA
authors.lastname: van der Meer
authors.forename: Senno
authors.initials: S
authors.lastname: Verhoef
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van't Veer
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010375:Pedigree; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53