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An entire exon 3 germ-line rearrangement in the BRCA2 gene: pathogenic relevance of exon 3 deletion in breast cancer predisposition

Danièle Muller1*, Etienne Rouleau2, Inès Schultz1, Sandrine Caputo2, Cédrick Lefol2, Ivan Bièche2, Olivier Caron3, Catherine Noguès4, Jean Marc Limacher3, Liliane Demange4, Rosette Lidereau2, Jean Pierre Fricker1 and Joseph Abecassis1

Author Affiliations

1 Division of oncogenetic, Department of Biology and Pathology, Regional Cancer Centre Paul Strauss, BP30042, 67065 Strasbourg, France

2 Oncogenetic laboratory, Institut Curie-Hospital René Huguenin, 92210 Saint Cloud, France

3 Department of oncology, Hôpitaux Universitaires de Strasbourg, 67071 Strasbourg, France

4 Clinical oncogenetic department, Institut Curie-Hospital René Huguenin, 92210 Saint Cloud, France

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BMC Medical Genetics 2011, 12:121  doi:10.1186/1471-2350-12-121

Published: 22 September 2011



Germ-line mutations in the BRCA1 and BRCA2 genes are major contributors to hereditary breast/ovarian cancer. Large rearrangements are less frequent in the BRCA2 gene than in BRCA1. We report, here, the first total deletion of exon 3 in the BRCA2 gene that was detected during screening of 2058 index cases from breast/ovarian cancer families for BRCA2 large rearrangements. Deletion of exon 3, which is in phase, does not alter the reading frame. Low levels of alternative transcripts lacking exon 3 (Δ3 delta3 transcript) have been reported in normal tissues, which raises the question whether deletion of exon 3 is pathogenic.


Large BRCA2 rearrangements were analysed by QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments) or MLPA (Multiplex Ligation-Dependent Probe Amplification). The exon 3 deletion was characterized with a "zoom-in" dedicated CGH array to the BRCA2 gene and sequencing. To determine the effect of exon 3 deletion and assess its pathogenic effect, three methods of transcript quantification were used: fragment analysis of FAM-labelled PCR products, specific allelic expression using an intron 2 polymorphism and competitive quantitative RT-PCR.


Large rearrangements of BRCA2 were detected in six index cases out of 2058 tested (3% of all deleterious BRCA2 mutations). This study reports the first large rearrangement of the BRCA2 gene that includes all of exon 3 and leads to an in frame deletion of exon 3 at the transcriptional level. Thirty five variants in exon 3 and junction regions of BRCA2 are also reported, that contribute to the interpretation of the pathogenicity of the deletion. The quantitative approaches showed that there are three classes of delta3 BRCA2 transcripts (low, moderate and exclusive). Exclusive expression of the delta3 transcript by the mutant allele and segregation data provide evidence for a causal effect of the exon 3 deletion.


This paper highlights that large rearrangements and total deletion of exon 3 in the BRCA2 gene could contribute to hereditary breast and/or ovarian cancer. In addition, our findings suggest that, to interpret the pathogenic effect of any variants of exon 3, both accurate transcript quantification and co-segregation analysis are required.