A tandem duplication of BRCA1 exons 1–19 through DHX8 exon 2 in four families with hereditary breast and ovarian cancer syndrome

Purpose The purpose of this study is to characterize a novel structural variant, a large duplication involving exons 1–19 of the BRCA1 gene in four independent families, and to provide diagnostically valuable information including the position of the breakpoints as well as clues to its clinical significance. Methods The duplication of exons 1–19 of the BRCA1 gene was initially detected by routine laboratory testing including MLPA analysis and next generation sequencing. For detailed characterization we performed array-comparative genome hybridization analysis, fluorescent in situ hybridization, next generation mapping, and long-distance PCR for break-point sequencing. Results Our data revealed a tandem duplication on chromosome 17 that encompassed 357 kb and included exons 1–19 of the BRCA1 gene and the genes NBR2 , NBR1 , TMEM106A , LOC100130581 , ARL4D , MIR2117 up to parts of the DHX8 gene. This structural variant appeared as a tandem duplication with breakpoints in intron 19 of the BRCA1 gene and in intron 3 of the DHX8 gene (HGVS:chr17(hg19):g.41210776_41568516dup). Segregation analysis indicated that this structural rearrangement is phased in trans with a known pathogenic exon deletion of the BRCA1 gene in one family. Conclusions The copy number variation initially recognized as duplication of exon 1–19 of the BRCA1 gene by MLPA analysis is a structural variation with breakpoints in the BRCA1 and DHX8 genes. Although currently to be classified as a variant of unknown significance, our family data indicates that this duplication may be a benign variation or at least of markedly reduced penetrance since it occurs in trans with another known fully pathogenic variant in the BRCA1 gene.