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Two major high-penetrance breast cancer genes,  BRCA1  and  BRCA2 , are responsible for approximately 20% of hereditary breast cancer (HBC) cases in Finland. Additionally, rare mutations in several other genes that interact with  BRCA1  and  BRCA2  increase the risk of HBC. Still, a majority of HBC cases remain unexplained which is challenging for genetic counseling. We aimed to analyze additional mutations in HBC-associated genes and to define the sensitivity of our current  BRCA1/2  mutation analysis protocol used in genetic counseling.    Methods  Eighty-two well-characterized, high-risk hereditary breast and/or ovarian cancer (HBOC)  BRCA1 / 2 -founder mutation-negative Finnish individuals, were screened for germline alterations in seven breast cancer susceptibility genes,  BRCA1 ,  BRCA2 ,  CHEK2 ,  PALB2 ,  BRIP1 ,  RAD50 , and  CDH1 .  BRCA1 / 2  were analyzed by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing.  CHEK2  was analyzed by the high resolution melt (HRM) method and  PALB2, RAD50, BRIP1  and  CDH1  were analyzed by direct sequencing. Carrier frequencies between 82 (HBOC)  BRCA1 / 2 -founder mutation-negative Finnish individuals and 384 healthy Finnish population controls were compared by using Fisher's exact test.  In silico  prediction for novel missense variants effects was carried out by using Pathogenic-Or-Not -Pipeline (PON-P).    Results  Three previously reported breast cancer-associated variants,  BRCA1  c.5095C > T,  CHEK2  c.470T > C, and  CHEK2  c.1100delC, were observed in eleven (13.4%) individuals. Ten of these individuals (12.2%) had  CHEK2  variants, c.470T > C and/or c.1100delC. Fourteen novel sequence alterations and nine individuals with more than one non-synonymous variant were identified. One of the novel variants,  BRCA2  c.72A > T (Leu24Phe) was predicted to be likely pathogenic  in silico . No large genomic rearrangements were detected in  BRCA1/2  by multiplex ligation-dependent probe amplification (MLPA).    Conclusions  In this study, mutations in previously known breast cancer susceptibility genes can explain 13.4% of the analyzed high-risk  BRCA1/2 -negative HBOC individuals.  CHEK2  mutations, c.470T > C and c.1100delC, make a considerable contribution (12.2%) to these high-risk individuals but further segregation analysis is needed to evaluate the clinical significance of these mutations before applying them in clinical use. Additionally, we identified novel variants that warrant additional studies. Our current genetic testing protocol for 28 Finnish  BRCA1/2 -founder mutations and protein truncation test (PTT) of the largest exons is sensitive enough for clinical use as a primary screening tool.

breast cancer research

Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high-risk Finnish BRCA1/2-founder mutation-negative breast and/or ovarian cancer individuals