Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls

Published:September 07, 2017DOI:


      • Ovarian cancer risks for mutations in hereditary cancer panel genes were assessed.
      • Mutations by gene from 7768 ovarian cancer cases and reference controls were compared.
      • BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, and RAD51D were confirmed as high-risk genes.
      • ATM was identified as a moderate risk ovarian cancer gene.
      • The results will inform clinical management of women with mutations these genes.



      Given the lack of adequate screening modalities, knowledge of ovarian cancer risks for carriers of pathogenic alterations in predisposition genes is important for decisions about risk-reduction by salpingo-oophorectomy. We sought to determine which genes assayed on multi-gene panels are associated with ovarian cancer, the magnitude of the associations, and for which clinically meaningful associations could be ruled out.


      7768 adult ovarian cancer cases of European ancestry referred to a single clinical testing laboratory underwent multi-gene panel testing for detection of pathogenic alterations in known or suspected ovarian cancer susceptibility genes. A targeted capture approach was employed to assay each of 19 genes for the presence of pathogenic or likely pathogenic alterations. Mutation frequencies in ovarian cancer cases were compared to mutation frequencies in individuals from the Exome Aggregation Consortium (ExAC). Analyses stratified by family and personal history of other cancers and age at diagnosis were also performed.


      Significant associations (p < 0.001) were identified between alterations in 11 genes and ovarian cancer, with eight of these displaying ≥5-fold increased risk (BRCA1, BRCA2, BRIP1, MSH2, MSH6, RAD51C, RAD51D). Relative risks of ovarian cancer greater than two-fold were also observed for ATM, but could reliably be ruled out for RAD50 and CHEK2.


      These results will inform clinical management of women found to carry pathogenic alterations in genes tested on multi-gene panels. The knowledge that some genes are not associated with OC can reduce concerns of women found to carry pathogenic alterations in those genes.


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