Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
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.
Borg
Ake
A
Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden. ake.borg@med.lu.se
Haile
Robert W
RW
Malone
Kathleen E
KE
Capanu
Marinela
M
Diep
Ahn
A
Törngren
Therese
T
Teraoka
Sharon
S
Begg
Colin B
CB
Thomas
Duncan C
DC
Concannon
Patrick
P
Mellemkjaer
Lene
L
Bernstein
Leslie
L
Tellhed
Lina
L
Xue
Shanyan
S
Olson
Eric R
ER
Liang
Xiaolin
X
Dolle
Jessica
J
Børresen-Dale
Anne-Lise
AL
Bernstein
Jonine L
JL
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
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human