Open Access Highly Accessed Research article

Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer

Hongxiu Wen1, Yeong C Kim1, Carrie Snyder2, Fengxia Xiao1, Elizabeth A Fleissner3, Dina Becirovic2, Jiangtao Luo4, Bradley Downs1, Simon Sherman3, Kenneth H Cowan3, Henry T Lynch125* and San Ming Wang13*

Author Affiliations

1 Department of Genetics, Cell Biology and Anatomy, College of Medicine, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA

2 Hereditary Cancer Center, Department of Preventive Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA

3 Fred & Pamela Buffett Cancer Center, Omaha, USA

4 Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, USA

5 Department of Medicine, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA

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BMC Cancer 2014, 14:470  doi:10.1186/1471-2407-14-470

Published: 26 June 2014



Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family.


In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer.


We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation.


Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.