title: Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
abstract: BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.
authors.affiliation: Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden. ake.borg@med.lu.se
authors.forename: Ake
authors.initials: A
authors.lastname: Borg
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Malone
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: Ahn
authors.initials: A
authors.lastname: Diep
authors.forename: Therese
authors.initials: T
authors.lastname: Törngren
authors.forename: Sharon
authors.initials: S
authors.lastname: Teraoka
authors.forename: Colin B
authors.initials: CB
authors.lastname: Begg
authors.forename: Duncan C
authors.initials: DC
authors.lastname: Thomas
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.forename: Lene
authors.initials: L
authors.lastname: Mellemkjaer
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.forename: Lina
authors.initials: L
authors.lastname: Tellhed
authors.forename: Shanyan
authors.initials: S
authors.lastname: Xue
authors.forename: Eric R
authors.initials: ER
authors.lastname: Olson
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Liang
authors.forename: Jessica
authors.initials: J
authors.lastname: Dolle
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Jonine L
authors.initials: JL
authors.lastname: Bernstein
mesh_terms: D000328:Adult; D000483:Alleles; D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D011485:Protein Binding
chemical_list: D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human