title: Evaluation of Fanconi Anemia genes in familial breast cancer predisposition.
abstract: Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and susceptibility to cancer. FA has eight known complementation groups and is caused by mutations in at least seven genes. Biallelic BRCA2 mutations were shown recently to cause FA-D1. Monoallelic (heterozygous) BRCA2 mutations confer a high risk of breast cancer and are a major cause of familial breast cancer. To investigate whether heterozygous variants in other FA genes are high penetrance breast cancer susceptibility alleles, we screened germ-line DNA from 88 BRCA1/2-negative families, each with at least three cases of breast cancer, for mutations in FANCA, FANCC, FANCD2, FANCE, FANCF, and FANCG. Sixty-nine sequence variants were identified of which 25 were exonic. None of the exonic variants resulted in translational frameshifts or nonsense codons and 14 were polymorphisms documented previously. Of the remaining 11 exonic variants, 2 resulted in synonymous changes, and 7 were present in controls. Only 2 conservative missense variants, 1 in FANCA and 1 in FANCE, were each found in a single family and were not present in 300 controls. The results indicate that FA gene mutations, other than in BRCA2, are unlikely to be a frequent cause of highly penetrant breast cancer predisposition.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Rita
authors.initials: R
authors.lastname: Barfoot
authors.forename: Hiran
authors.initials: H
authors.lastname: Jayatilake
authors.forename: Paula
authors.initials: P
authors.lastname: Smith
authors.forename: Anthony
authors.initials: A
authors.lastname: Renwick
authors.forename: Linda
authors.initials: L
authors.lastname: Bascombe
authors.forename: Lesley
authors.initials: L
authors.lastname: McGuffog
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D005199:Fanconi Anemia / Q000235:genetics*; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D052219:Fanconi Anemia Complementation Group F Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D011506:Proteins / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; C499905:FANCD2 protein, human; C499907:FANCE protein, human; C499901:FANCF protein, human; C499909:FANCG protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052239:Fanconi Anemia Complementation Group E Protein; D052219:Fanconi Anemia Complementation Group F Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016601:RNA-Binding Proteins