germline variants in early-onset breast cancer patients from hereditary breast and ovarian cancer families.

, located 470 kb downstream of , encodes for the nuclear PSMC3-interacting protein, which functions as co-activator of steroid hormone-mediated gene expression, and is involved in RAD51 and DMC1-mediated homologous recombination during DNA repair of double-strand breaks. Recently, germline variants in have been identified in hereditary breast and ovarian cancer (HBOC) patients, mainly in cases with early-onset. We screened a cohort of 166 mutation-negative HBOC patients, of which 56 developed early-onset breast cancer before the age of 36 years, for variants. We identified 7 novel or rare variants in 8 out of 166 index patients: c.-115G>A (rs191843707); c.-70T>A (rs752276800); c.-37A>T (rs199620968); c.-24C>G (rs200359709); c.519G>A p.(Trp173*); c.537+51G>C (rs375509656); c.*24G>A. Three out of 7 identified variants (c.-115G>A, c.519G>A and c.*24G>A) with putative pathogenic impact were found in HBOC patients with breast cancer onset at ≤ 36 years. The nonsense mutation c.519G>A p.(Trp173*) was located within the DNA binding domain of GT198 and is predicted to induce nonsense-mediated mRNA decay. Functional analyses of c.-115G>A, and c.*24A>G indicated an influence of these variants on gene expression. This is the second study that gives evidence for an association between pathogenic germline variants and early-onset breast cancer in HBOC.