title: Multigene testing of moderate-risk genes: be mindful of the missense.
abstract: Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established.
  
  
  
  We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold.
  
  
  
  Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5.
  
  
  
  Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Young
authors.affiliation: Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Feng
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Stark
authors.affiliation: Breast Cancer Genetics Group, Cancer Research Centre of Lyon, Centre Léon Bérard, Lyon, France.
authors.forename: F
authors.initials: F
authors.lastname: Damiola
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: G
authors.initials: G
authors.lastname: Durand
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Forey
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Francy
authors.affiliation: Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gammon
authors.affiliation: Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: W K
authors.initials: WK
authors.lastname: Kohlmann
authors.affiliation: Department of Communication and Huntsman Cancer Institute, University of Utah.
authors.forename: K A
authors.initials: KA
authors.lastname: Kaphingst
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: S
authors.initials: S
authors.lastname: McKay-Chopin
authors.affiliation: Genetic Epidemiology Laboratory, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Nguyen-Dumont
authors.affiliation: Instituto de Ciencias Básicas y Medicina Experimental del Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
authors.forename: J
authors.initials: J
authors.lastname: Oliver
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Paquette
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: M
authors.initials: M
authors.lastname: Pertesi
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Robinot
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Rosenthal
authors.affiliation: Cancer Genomics Laboratory, CHUQ Research Center, Quebec City, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Vallee
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Voegele
authors.affiliation: Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia Department of Epidemiology (Genome Epidemiology Lab), Seoul National University School of Public Health, Seoul, Korea.
authors.forename: J L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Department of Communication and Huntsman Cancer Institute, University of Utah.
authors.forename: M C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Department of Molecular Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: I L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Cancer Prevention Institute of California, Fremont, California, USA Department of Health Research and Policy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: John
authors.affiliation: Department of Family and Preventive Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hashibe
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gertz
authors.affiliation: Genetic Cancer Susceptibility group, International Agency for Research on Cancer, Lyon, France.
authors.forename: F
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: Genetic Epidemiology of Cancer Team, Inserm, U900, Institut Curie, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Lesueur
authors.affiliation: Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Goldgar
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Tavtigian
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk
keywords: Cancer: breast; Clinical genetics; Genetics; Screening