Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.

p53 Germline mutation in a patient with Li-Fraumeni Syndrome and three metachronous malignancies.

PURPOSE: Germline mutations of the p53 coding region are present in approximately 50-70% of patients with Li-Fraumeni Syndrome (LFS), a rare hereditary disorder of familial and intraindividual clustering of different malignancies such as sarcoma (index tumor), breast cancer, brain tumors, leukemias, and adrenocortical carcinomas, the latter usually in young children. Both onset and spectrum of malignancies in individuals with LFS are thus heterogenous and may, less frequently, also include other epithelial and mesenchymal tumors. A 32-year-old female presented for genetic counseling with a history of leiomyosarcoma at age 22, malignant melanoma (a rare component of LFS) at age 26, and breast cancer at age 30. All three tumors had been treated surgically. Astrocytoma and breast cancer, respectively, had been diagnosed in her brother and mother before age 30. Other malignancies diagnosed early in life in relatives of the mother were: prostate cancer, stomach cancer, and carcinoma of the larynx. METHODS: Upon written informed consent, DNA was extracted from peripheral blood mononuclear cells of the proband, and p53 exons 4-8 analyzed for mutations by SSCP and DNA sequencing. RESULTS: A G:C to A:T mutation at codon 175 of p53 resulting in an arginine --> histidine substitution was detected, confirming the clinical diagnosis of LFS. CONCLUSIONS: The patient and her family are being followed further, but testing of her children for the presence of this mutation is currently being withheld. The difficulties in the management and treatment of patients with this clinically heterogenous disorder are discussed.