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

  • Epidemiology
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Abstract

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.

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Abbreviations

VUS:

Variant of uncertain significance

UCV or UV:

Unclassified variant

BRCA:

Breast cancer gene

BC:

Breast cancer

OC:

Ovarian cancer

PC:

Pancreatic cancer

LC:

Lung cancer

NMD:

Nonsense-mediated RNA decay

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Acknowledgments

We thank the families and the blood donors for providing samples for this study. We also acknowledge the support of Dr. Rongxi Yang and the excellent technical assistance of Claudia Dinkelacker, Yvonne Kilian, Kerstin Lang, Gloria Luta, and Sabine Serick. This study was supported by the Dietmar-Hopp Foundation, the Helmholtz-Society, the German Cancer Aid, and the German Cancer Research Center (DKFZ).

Conflict of interest

All authors declared that they have no conflict of interest.

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Authors and Affiliations

  1. Division Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, University of Heidelberg, Vossstrasse 9, 69115, Heidelberg, Germany

    Michelle G. Rath, Anne Langheinz, Sandrine Tchatchou & Barbara Burwinkel

  2. Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 581, 69120, Heidelberg, Germany

    Anne Langheinz, Sandrine Tchatchou & Barbara Burwinkel

  3. Department of Gynecology and Obstetrics, University of Heidelberg, Voßstrasse 9, 69115, Heidelberg, Germany

    Michelle G. Rath, Jörg Heil, Michael Golatta, Sarah Schott, Teresa Drasseck, Hans Junkermann, Andreas Schneeweiss & Christof Sohn

  4. Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany

    Farnoosh Fathali-Zadeh, Theda Voigtländer, Anne Behnecke, Anna-Lena Burgemeister, Christina Evers, Claus R. Bartram & Christian Sutter

  5. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service Baden-Wuerttemberg—Hessen, Friedrich-Ebert-Str. 107, 68167, Mannheim, Germany

    Peter Bugert

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  1. Michelle G. Rath
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  2. Farnoosh Fathali-Zadeh
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Correspondence to Barbara Burwinkel.

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Michelle G. Rath, Farnoosh Fathali-Zadeh, Christian Sutter and Barbara Burwinkel contributed equally to this work.

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Rath, M.G., Fathali-Zadeh, F., Langheinz, A. et al. Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene. Breast Cancer Res Treat 133, 725–734 (2012). https://doi.org/10.1007/s10549-011-1917-0

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