Li-Fraumeni Syndrome 2

A number sign (#) is used with this entry because Li-Fraumeni syndrome-2 is caused by heterozygous mutation in the CHEK2 gene (604373) on chromosome 22q12.

For a general phenotypic description and a discussion of genetic heterogeneity of Li-Fraumeni syndrome (LFS), see LFS1 (151623).

In affected members of 3 unrelated families, 1 family with classic LFS and 2 with LFS-variant, without mutations in the TP53 gene (191170), Bell et al. (1999) identified heterozygous germline mutations in the CHK2 gene (see, e.g., 604373.0001 and 604373.0002). They defined LFS-variant as the occurrence in an individual of 3 separate primary cancers, with the first cancer diagnosed under age 45 years, or the combination of a proband with childhood cancer or LFS component tumor diagnosed under age 45 years, a first- or second-degree relative with LFS component tumor diagnosed at any age, and a first- or second-degree relative with any cancer diagnosed under age 60 years. CHK2 is a homolog of Saccharomyces cerevisiae RAD53 and Schizosaccharomyces pombe cds1+, protein kinases required for DNA damage and replication checkpoints.

Vahteristo et al. (2001) reported 2 Finnish families with LFS and a mutation in the CHK gene. The phenotype in both families was considered atypical because of the lack of sarcomas or childhood cancers.

Vahteristo et al. (2001) analyzed the CHK1 (603078), CHK2, and p53 genes for mutations in 44 Finnish families with Li-Fraumeni syndrome, Li-Fraumeni-like syndrome, or a phenotype suggestive of Li-Fraumeni syndrome. Five different disease-causing mutations were observed in 7 families: 4 in the p53 gene and 1 in the CHK2 gene. The CHK2 mutation occurred in 2 families and was the same as the mutation reported by Bell et al. (1999) in a family with classic LFS: 1100delC (604373.0001). The families originated from different parts of Finland, were not known to be related, and segregated different chromosome 22 haplotypes. Thus, 1100delC is clearly a disease-causing mutation and represents a mutation hotspot in the CHK2 gene.