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Background  Germ line mutations in  BRCA1  and  BRCA2  ( BRCA1/2 ) and other susceptibility genes have been identified as genetic causes of hereditary breast and ovarian cancer (HBOC). To identify the disease-causing mutations in a cohort of 120 Brazilian women fulfilling criteria for HBOC, we carried out a comprehensive screening of  BRCA1/2 ,  TP53  R337H,  CHEK2  1100delC, followed by an analysis of copy number variations in 14 additional breast cancer susceptibility genes ( PTEN ,  ATM ,  NBN ,  RAD50 ,  RAD51 ,  BRIP1 ,  PALB2 ,  MLH1 ,  MSH2 ,  MSH6 ,  TP53 ,  CDKN2A ,  CDH1  and  CTNNB1 ).    Methods  Capillary sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for detecting point mutations and copy number variations (CNVs), respectively, for the  BRCA1  and  BRCA2  genes; capillary sequencing was used for point mutation for both variants  TP53  R337H and  CHEK2  1100delC, and finally array comparative genomic hybridization (array-CGH) was used for identifying CNVs in the 14 additional genes.    Results  The positive detection rate in our series was 26%.  BRCA1  pathogenic mutations were found in 20 cases, including two cases with CNVs, whereas  BRCA2  mutations were found in 7 cases. We also found three patients with the  TP53  R337H mutation and one patient with the  CHEK2  1100delC mutation. Seven (25%) pathogenic mutations in  BRCA1/2  were firstly described, including a splice-site  BRCA1  mutation for which pathogenicity was confirmed by the presence of an aberrant transcript showing the loss of the last 62 bp of exon 7. Microdeletions of exon 4 in  ATM  and exon 2 in  PTEN  were identified in  BRCA2 -mutated and  BRCA1/2 -negative patients, respectively.    Conclusions  In summary, our results showed a high frequency of  BRCA1/2  mutations and a higher prevalence of  BRCA1  (64.5%) gene. Moreover, the detection of the  TP53  R337H variant in our series and the fact that this variant has a founder effect in our population prompted us to suggest that all female breast cancer patients with clinical criteria for HBOC and negative for  BRCA1/2  genes should be tested for the  TP53  R337H variant. Furthermore, the presence of genomic structural rearrangement resulting in CNVs in other genes that predispose breast cancer in conjunction with  BRCA2  point mutations demonstrated a highly complex genetic etiology in Brazilian breast cancer families.

Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients