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Background  The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern.  BRCA1  and  BRCA2  are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20–30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in  ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN,  and  TP53  genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients.    Methods  We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways ( ABRAXAS1 ,  ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53  and  UIMC1 ). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in  BRCA1 / BRCA2  genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms.    Results  We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in  BRCA1, BRCA2  and  TP53 , a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in  ATR , which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in  ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2,  and  PMS2  genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in  BRCA1/BRCA2  genes.    Conclusions  This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.

bmc medical genomics

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population