Inherited Mutations in Breast Cancer Genes—Risk and Response

  • Andrew Y. Shuen
  • William D. FoulkesEmail author


Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases. Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates. The “missing heritability” is thought to be due to cumulative effects of susceptibility alleles associated with low to moderate penetrance, in accordance with a polygenic model of inheritance. In addition, a large number of individually very rare, highly penetrant variants could account for part of the gap. Meanwhile, an understanding of the function of BRCA1 and BRCA2 in the DNA damage response pathway has lead to the identification of a number of breast cancer susceptibility genes including PALB2, CHEK2, ATM and BRIP1, all of which interact directly or indirectly with BRCA1 or BRCA2. Knowledge of how BRCA1 and BRCA2 maintain genomic integrity has also led the development of novel targeted therapies. Here we summarize the recent advances made in the understanding of the functions of these two genes, as well as the risks and responses associated with mutations in these and other breast cancer susceptibility genes.


BRCA1 BRCA2 Breast cancer susceptibility genes PARP inhibitors Cisplatin 



Ataxia telangiectasia mutated


Breast cancer susceptibility gene 1


Breast cancer susceptibility gene 2


BRCA1-interacting protein 1


C terminal binding protein


Double strand break


Estrogen receptor


Genome-wide association study


Human epidermal growth factor receptor


Homologous repair




Odds ratio


Partner and localizer of BRCA2


Poly (ADP-ribose) polymerase


Pathologic complete response


Progesterone receptor


Really interesting new gene


Single nucleotide polymorphism


Small ubiquitin-like modifier


Triple negative breast cancer



We thank Marc Tischkowitz MB.BCh. Ph.D for helpful comments.

Work carried out in Dr. Foulkes’ laboratory is supported by Susan G. Komen for the Cure.


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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Medical GeneticsMcGill University Health CentreMontrealCanada
  2. 2.Program in Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in OncologyMcGill UniversityMontrealCanada
  3. 3.Department of Medical Genetics and Lady Davis InstituteJewish General HospitalMontrealCanada

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