Abstract P5-10-04: Exome sequencing in high breast and ovarian cancer incidence families which lack detectable mutations in established cancer susceptibility genes

Abstract

Abstract At our center, a standard 25 gene panel has proved useful for the identification of pathogenic germline mutations in many families with a high penetrance of breast and ovarian cancer, yet there remain several families with very high cancer incidence but from whom these assays have not identified pathogenic alleles. To attempt to define the genetic mechanism of susceptibility in such cases, are conducting germline whole exome sequencing in affected individuals. Here we describe the identification of strong candidate susceptibility variants in two such families. Both variants cause loss-of-function of DNA repair genes not previously implicated in breast cancer, but which share properties with genes with known roles in maintenance of genome integrity. In one individual, with a personal history of ovarian cancer and two independent breast tumors, we identified a novel point mutation in POLD2 which introduces a mutation at a residue which is biochemically conserved in all animal species thus far sequenced. In the second individual, a frameshift mutation was detected in ERCC4. In both cases, the variants found have not been observed in large exome datasets (e.g. ExAC) or reported in ClinVar. Our study highlights the potential utility of whole exome sequencing as a discovery tool in those families with high cancer incidence yet which lack mutations in known hereditary cancer predisposition genes. Citation Format: Kenny PA, Girtman MA, Deviley JA, Meier DR, Vos CR, Richmond CS, Lofgren KA. Exome sequencing in high breast and ovarian cancer incidence families which lack detectable mutations in established cancer susceptibility genes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-04.