title: About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants.
abstract: RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.667+2_667+23del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.667+2_667+23del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family.
authors.forename: Sara
authors.initials: S
authors.lastname: Gutiérrez-Enríquez
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonache
authors.forename: Gorka Ruíz
authors.initials: GR
authors.lastname: de Garibay
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: Marta
authors.initials: M
authors.lastname: Santamariña
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramón y Cajal
authors.forename: Eva
authors.initials: E
authors.lastname: Esteban-Cardeñosa
authors.forename: Anna
authors.initials: A
authors.lastname: Tenés
authors.forename: Kira
authors.initials: K
authors.lastname: Yanowsky
authors.forename: Alicia
authors.initials: A
authors.lastname: Barroso
authors.forename: Gemma
authors.initials: G
authors.lastname: Montalban
authors.forename: Ana
authors.initials: A
authors.lastname: Blanco
authors.forename: Mònica
authors.initials: M
authors.lastname: Cornet
authors.forename: Neus
authors.initials: N
authors.lastname: Gadea
authors.forename: Mar
authors.initials: M
authors.lastname: Infante
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Judith
authors.initials: J
authors.lastname: Balmaña
authors.forename: Adriana
authors.initials: A
authors.lastname: Lasa
authors.forename: Ana
authors.initials: A
authors.lastname: Vega
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Orland
authors.initials: O
authors.lastname: Diez
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D013030:Spain
chemical_list: D004268:DNA-Binding Proteins; C112629:RAD51D protein, human