title: Functional evaluation and cancer risk assessment of BRCA2 unclassified variants.
abstract: The influence of germ line BRCA2 unclassified variants (UCV), including missense mutations and in-frame deletions and insertions on BRCA2 function and on cancer risk, has not been defined although these mutations account for 43% of all identified BRCA2 sequence alterations. To investigate the effects of UCVs on BRCA2 function, we compared mutant and wild-type forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, and genome instability. We confirm that the effects of known deleterious mutations can be distinguished from neutral polymorphisms and wild-type BRCA2 in these assays, and we characterize the influence of a series of UCVs on BRCA2 function. We also describe how the results from the assays can be combined with data from analysis of cosegregation of the UCVs with cancer, co-occurrence of the UCVs with other deleterious mutations, and interspecies sequence variation in a comprehensive framework in an effort to better distinguish between disease predisposing and neutral UCVs. This combined approach represents a useful means of addressing the functional significance and cancer relevance of UCVs in BRCA2.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Kangjian
authors.initials: K
authors.lastname: Wu
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Hinson
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.forename: Daniel
authors.initials: D
authors.lastname: Farrugia
authors.forename: Patricia
authors.initials: P
authors.lastname: Wendt
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Amie
authors.initials: A
authors.lastname: Deffenbaugh
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D018385:Centrosome / Q000502:physiology; D020090:Chromosome Segregation; D003432:Cross-Linking Reagents / Q000009:adverse effects; D018076:DNA, Complementary / Q000235:genetics; D004342:Drug Hypersensitivity / Q000235:genetics; D005784:Gene Amplification; D024522:Genes, BRCA2 / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D016685:Mitomycin / Q000009:adverse effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D016415:Sequence Alignment; D014162:Transfection
chemical_list: D024682:BRCA2 Protein; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D016685:Mitomycin