Mutations in BRCA1 and BRCA2 account for approximately 50% of breast/ovarian cancer pedigrees with more than four affected cases , whereas mutations in PTEN , CHK2  and ATM  have been reported in a small number of breast cancer families or women with early onset breast cancer. In addition, germ line missense mutations in the p53 gene are associated with Li Fraumeni syndrome, a feature of which is early onset breast cancer . The p53 gene is the most commonly mutated gene in human malignancies and has many important biological functions, including the control of cell cycle checkpoint after DNA damage. Deleterious germ line mutations in the p53 gene are found in less than 1% of all breast cancer patients, suggesting that the contribution of exonic mutations to familial breast cancer risk is small [6,7,8,9,10]. However, mutations in regulatory regions of the gene may affect p53 expression and thereby increase the risk of disease.
One candidate for such a mutation is the G13964C variant in intron 6 of the p53 gene, which has been reported in 3 out of 42 patients with hereditary breast cancer (including a CC homozygote affected at age 59 years) but in none of 171 sporadic breast cancer patients (P = 0.0003) . All three patients with the p53 variant had strong family histories that were consistent with Li Fraumeni syndrome but had a late age at onset.
Intronic variants may affect gene regulation through aberrant splicing or through disruption of critical DNA–protein interactions . The p53 G13964C variant is not within the consensus splice site and there is thus far no direct evidence that it affects the expression of p53. It is not associated with over-expression of p53 , which is a hallmark of missense mutations in p53. Nonetheless, there is some indirect evidence that this variant has a functional role . Functional analysis using an in vitro cell survival assay demonstrated that lymphophoblastoid cell lines derived from patients with the G13964C variant exhibited a reduced level of apoptosis after chemotherapy and prolonged cell survival following DNA damage.
In order to determine the importance of the G13964C p53 variant in multiple-case Australian breast cancer families, we genotyped this variant in the youngest affected member of 71 breast cancer families and 143 control individuals. Our results suggest that the rare 13964C allele is no more common in breast cancer families than in control individuals. This suggests that the variant is not a high-risk mutation but, as suggested previously , is more likely to be a benign polymorphism.