title: Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1.
abstract: Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Delta exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Delta exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together, a combined approach of functional and bioinformatics analysis, plus structural modeling, can be utilized to obtain valuable information pertaining to the effect of a rare variant on the structure and function of BRCA1. Such information can, in turn, aid in the classification of BRCA1 variants for which there is a lack of genetic information needed to provide reliable risk assessment.
authors.affiliation: H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Carvalho
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pino
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beddor
authors.forename: Martha
authors.initials: M
authors.lastname: Godinho-Netto
authors.forename: Rafael D
authors.initials: RD
authors.lastname: Mesquita
authors.forename: Renato S
authors.initials: RS
authors.lastname: Rodarte
authors.forename: Danielle C
authors.initials: DC
authors.lastname: Vaz
authors.forename: Viviane A
authors.initials: VA
authors.lastname: Monteiro
authors.forename: Siranoush
authors.initials: S
authors.lastname: Manoukian
authors.forename: Mara
authors.initials: M
authors.lastname: Colombo
authors.forename: Carla B
authors.initials: CB
authors.lastname: Ripamonti
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.forename: Graeme
authors.initials: G
authors.lastname: Suthers
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Paolo
authors.initials: P
authors.lastname: Radice
authors.forename: Scott A
authors.initials: SA
authors.lastname: Grist
authors.forename: Alvaro N A
authors.initials: AN
authors.lastname: Monteiro
authors.forename: Blase
authors.initials: B
authors.lastname: Billack
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D019295:Computational Biology; D003198:Computer Simulation; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008957:Models, Genetic; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion / Q000235:genetics*; D014162:Transfection
chemical_list: D019313:BRCA1 Protein