title: RAD51C germline mutations found in Spanish site-specific breast cancer and breast-ovarian cancer families.
abstract: BRCA1 and BRCA2 are the most well-known breast and ovarian cancer susceptibility genes. Additional genes involved in DNA repair have been identified as predisposing to breast cancer. Recently, RAD51C, a new Fanconi Anemia gene, essential for homologous recombination repair, has been reported to be a rare hereditary breast and ovarian cancer susceptibility gene. Indeed, several pathogenic mutations have been identified in BRCA1/BRCA2-negative hereditary breast and ovarian cancer families. Here, we present the results of the screening of RAD51C mutations in a large series of 516 BRCA1/BRCA2-negative Spanish patients from breast and/or ovarian cancer families, and the evaluation of these results in the context of all RAD51C carriers. RAD51C mutation screening was performed by DNA analysis for all index cases. All the genetic variants identified were analyzed in silico for splicing and protein predictions. cDNA analysis was performed for three selected variants. All previous RAD51C mutation studies on breast and/or ovarian cancer were reviewed. We identified three inactivating RAD51C mutations. Two mutations were found in breast and ovarian cancer families and one mutation in a site-specific breast cancer family. Based on the mean age of ovarian cancer diagnosis in RAD51C carriers, we would recommend prophylactic bilateral salpingo-ophorectomy in premenopausal RAD51C mutation carriers. Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer. Thus, RAD51C testing should be offered to hereditary breast and/or ovarian cancer families without selecting for specific cancer origin.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica-Servicio Galego de Saúde, Grupo de Medicina Xenómica-Universidade de Santiago de Compostela, Spanish Network on Rare Diseases (CIBERER), Instituto de Investigaciones Sanitarias de Santiago, Santiago de Compostela, A Coruña, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Blanco
authors.forename: Sara
authors.initials: S
authors.lastname: Gutiérrez-Enríquez
authors.forename: Marta
authors.initials: M
authors.lastname: Santamariña
authors.forename: Gemma
authors.initials: G
authors.lastname: Montalban
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonache
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Orland
authors.initials: O
authors.lastname: Diez
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D011379:Prognosis; D013030:Spain / Q000453:epidemiology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C448305:RAD51C protein, human