title: Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene.
abstract: There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility.
  
  
  
  Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer.
  
  
  
  Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited.
  
  
  
  ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.
authors.affiliation: Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Tavera-Tapia
authors.affiliation: Medical Genetics Unit, Sistemas Genómicos, Parque Tecnológico de Valencia, Ronda G. Marconi 6, 46980, Paterna, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Pérez-Cabornero
authors.affiliation: Hereditary Cancer Unit, Medical Oncology Service, Hospital Morales Meseguer, Av Marqués de los Vélez, s/n, 30008, Murcia, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Macías
authors.affiliation: Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: M I
authors.initials: MI
authors.lastname: Ceballos
authors.affiliation: Monoclonal Antibody Unit, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Roncador
authors.affiliation: Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, Calle del Prof Martín Lagos, s/n, 28040, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: de la Hoya
authors.affiliation: Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Barroso
authors.affiliation: Medical Genetics Unit, Sistemas Genómicos, Parque Tecnológico de Valencia, Ronda G. Marconi 6, 46980, Paterna, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Felipe-Ponce
authors.affiliation: Medical Oncology Department, Hospital Reina Sofía, Av. Menéndez Pidal s/n, 14004, Córdoba, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Serrano-Blanch
authors.affiliation: Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Av. de Valdecilla, s/n, 39008, Santander, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Hinojo
authors.affiliation: Medical Genetics Unit, Biochemistry Service, Miguel Servet Hospital, Paseo Isabel la Católica, 1-3, 50009, Saragossa, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Miramar-Gallart
authors.affiliation: Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, Calle del Prof Martín Lagos, s/n, 28040, Madrid, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Caldés
authors.affiliation: Medical Genetics Unit, Sistemas Genómicos, Parque Tecnológico de Valencia, Ronda G. Marconi 6, 46980, Paterna, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Santillan-Garzón
authors.affiliation: Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.|Spanish Network on Rare Diseases (CIBERER), Monforte de Lemos 3-5. Pabellón 11. Planta 0, 28029, Madrid, Spain.|Genotyping Unit, CEGEN, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Benitez
authors.affiliation: Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Melchor Fernández Almagro 3, 28029, Madrid, Spain. aosorio@cnio.es.|Spanish Network on Rare Diseases (CIBERER), Monforte de Lemos 3-5. Pabellón 11. Planta 0, 28029, Madrid, Spain. aosorio@cnio.es.
authors.forename: A
authors.identifier: 0000-0001-8124-3984
authors.initials: A
authors.lastname: Osorio
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010375:Pedigree; D015995:Prevalence; D013030:Spain / Q000453:epidemiology; D000073359:Exome Sequencing
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; Germline pathogenic variant; Hereditary breast and ovarian cancer; Whole exome sequencing