title: FAN1 variants identified in multiple-case early-onset breast cancer families via exome sequencing: no evidence for association with risk for breast cancer.
abstract: We are interested in the characterisation of previously undescribed contributions to the heritable component of human cancers. To this end, we applied whole-exome capture, followed by massively parallel sequence analysis to the germline DNA of two greater than third-degree affected relatives from four multiple-case, early-onset breast cancer families. Prior testing for variants in known breast cancer susceptibility, genes in these families did not identify causal mutations. We detected and confirmed two different variants in the DNA damage repair gene FAN1 (R377W, chr15:31197995 C>T and R507H, chr15:31202961 G>A [hg19]) which were not present in dbSNP131. In one family, FAN1 R377W, predicted to be damaging by SIFT and PolyPhen2, was present in all six tested members with cancer (five with breast cancer, one with malignant melanoma). In another family, FAN1 R507H, predicted to be damaging by SIFT but benign by PolyPhen2, was observed in one of two tested members with breast cancer. We genotyped FAN1 R377W and R507H variants across 1417 population-based cases and 1490 unaffected population-based controls (frequency-matched for age). These variants were rare in the Australian population (minor allele frequencies of 0.0064 and 0.010, respectively) and were not associated with breast cancer risk (OR = 0.80, 95% CI[0.39-1.61], P = 0.50 and OR = 0.74, 95% CI[0.41-1.29], P = 0.26, respectively). Analysis of breast cancer risks for relatives of case and control carriers did not find evidence of an increased risk. Despite the biological role of FAN1, the plausibility of its role as a breast cancer predisposition gene, and the possible deleterious nature of the identified variants, these two variants do not appear to be causal for breast cancer. Future studies to extend the genetic analysis of FAN1 will further explore its possible role as a breast cancer susceptibility gene.
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia. djp@unimelb.edu.au
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Park
authors.forename: Fabrice A
authors.initials: FA
authors.lastname: Odefrey
authors.forename: Fleur
authors.initials: F
authors.lastname: Hammet
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.lastname: ABCFS
authors.lastname: MCCS
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schmidt
authors.forename: Enes
authors.initials: E
authors.lastname: Makalic
authors.forename: Olga M
authors.initials: OM
authors.lastname: Sinilnikova
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D001315:Australia / Q000453:epidemiology; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D064251:Multifunctional Enzymes; D010375:Pedigree
chemical_list: D064251:Multifunctional Enzymes; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C551063:FAN1 protein, human