Molecular Genetic Characteristics of FANCI , a Proposed New Ovarian Cancer Predisposing Gene.

was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of c.1813C>T; p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery c.1813C>T; p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in , , , , , and , which identified four candidate variants. We then investigated in high-grade serous ovarian carcinoma (HGSC) from c.1813C>T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from c.1813C>T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as and are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline c.1813C>T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls ( = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying c.1813C>T; p.L605F and suggest the possible involvement of in other cancer types at the germline and/or somatic level.