Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families

Fam Cancer. 2012 Sep;11(3):483-91. doi: 10.1007/s10689-012-9540-8.


Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. BRIP1 and PALB2 are likely genes for breast cancer susceptibility, based on their roles in maintaining cellular integrity. Indeed, few pathogenic germline mutations in both genes are reported in ethnically diverse breast cancer families. There is a paucity of data on the putative contribution of both genes to inherited breast cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were screened for BRIP1 germline mutations by combined denaturing gradient gel electrophoresis, high resolution melting and sequencing. Direct sequencing of exons and flanking intronic sequences was used for PALB2 mutational analysis. Overall, 149 women, all of high risk, cancer prone families of Ashkenazi origin, were genotyped for BRIP1 mutations: 127 with breast cancer, 22 with ovarian cancer. No truncating mutations were noted and one novel (p.Ala745Thr) and two previously described missense mutations were detected. For PALB2, 93 women were genotyped (87 with breast cancer) of Ashkenazi (n = 32) and non Ashkenazi Jewish origin. Fifteen sequence variants were detected, of these, none was truncating, four were not previously reported, and two (p.Asp871Gly and p.Leu1119Pro) were seemingly pathogenic based on the PolyPhen2 protein prediction algorithm. These missense mutations were not detected in any of 113 healthy Ashkenazi and 109 Moroccan, cancer free controls. In conclusion, germline mutations in BRIP1 and PALB2 contribute marginally to breast cancer susceptibility in ethnically diverse, Jewish high risk families.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Breast Neoplasms / genetics*
  • Case-Control Studies
  • DNA-Binding Proteins / genetics*
  • Exons
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Female
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • Humans
  • Jews / genetics*
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Ovarian Neoplasms / genetics*
  • RNA Helicases / genetics*
  • Tumor Suppressor Proteins / genetics*


  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Fanconi Anemia Complementation Group Proteins
  • Nuclear Proteins
  • PALB2 protein, human
  • Tumor Suppressor Proteins
  • BRIP1 protein, human
  • RNA Helicases