title: BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X.
abstract: Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon-intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.
authors.affiliation: Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, IdISSC, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Garre
authors.forename: L
authors.initials: L
authors.lastname: Martín
authors.forename: J
authors.initials: J
authors.lastname: Sanz
authors.forename: A
authors.initials: A
authors.lastname: Romero
authors.forename: A
authors.initials: A
authors.lastname: Tosar
authors.forename: I
authors.initials: I
authors.lastname: Bando
authors.forename: P
authors.initials: P
authors.lastname: Llovet
authors.forename: P
authors.initials: P
authors.lastname: Diaque
authors.forename: B
authors.initials: B
authors.lastname: García-Paredes
authors.forename: E
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: M
authors.initials: M
authors.lastname: de la Hoya
authors.forename: T
authors.initials: T
authors.lastname: Caldés
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D024682:BRCA2 Protein / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000235:genetics*; D005190:Family; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D024682:BRCA2 Protein
keywords: BRCA2; cancer susceptibility; familial colorectal cancer; risk alleles