title: Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.
abstract: BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53, and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize noncoding variants of uncertain significance in regulatory, coding, and intronic regions based on changes in binding sites in these genes. Besides mRNA splicing, IT provides a common framework to evaluate potential affinity changes in transcription factor (TFBSs), splicing regulatory (SRBSs), and RNA-binding protein (RBBSs) binding sites following mutation. We prioritized variants affecting the strengths of 10 splice sites (four natural, six cryptic), 148 SRBS, 36 TFBS, and 31 RBBS. Three variants were also prioritized based on their predicted effects on mRNA secondary (2°) structure and 17 for pseudoexon activation. Additionally, four frameshift, two in-frame deletions, and five stop-gain mutations were identified. When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and co-segregation analysis.
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Natasha G
authors.initials: NG
authors.lastname: Caminsky
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Eliseos J
authors.initials: EJ
authors.lastname: Mucaki
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Ami M
authors.initials: AM
authors.lastname: Perri
authors.affiliation: Department of Computer Science, Faculty of Science, Western University, London, Ontario, Canada.
authors.forename: Ruipeng
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Cytognomix Inc, London, Ontario, Canada.
authors.forename: Joan H M
authors.initials: JH
authors.lastname: Knoll
authors.affiliation: Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.|Department of Computer Science, Faculty of Science, Western University, London, Ontario, Canada.|Cytognomix Inc, London, Ontario, Canada.|Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Rogan
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009690:Nucleic Acid Conformation; D012326:RNA Splicing; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D012333:RNA, Messenger
keywords: 3′ untranslated region; RNA stability; breast neoplasm; genetic testing; information theory; ovarian; tumor suppressor