1098-10043132010MarHuman mutationHum MutatCharacterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.E1200-4010.1002/humu.21202BRCA1 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.(c) 2010 Wiley-Liss, Inc.BorgAkeADepartment of Oncology, Clinical Sciences, Lund University, Lund, Sweden. ake.borg@med.lu.seHaileRobert WRWMaloneKathleen EKECapanuMarinelaMDiepAhnATörngrenThereseTTeraokaSharonSBeggColin BCBThomasDuncan CDCConcannonPatrickPMellemkjaerLeneLBernsteinLeslieLTellhedLinaLXueShanyanSOlsonEric RERLiangXiaolinXDolleJessicaJBørresen-DaleAnne-LiseALBernsteinJonine LJLengR01 CA131010CANCI NIH HHSUnited StatesR01 CA097397CANCI NIH HHSUnited StatesR01 CA097397-05CANCI NIH HHSUnited StatesR01 CA131010-02CANCI NIH HHSUnited StatesR01 CA098438CANCI NIH HHSUnited StatesCA097397CANCI NIH HHSUnited StatesR01 CA129639CANCI NIH HHSUnited StatesCA098438CANCI NIH HHSUnited StatesCA131010CANCI NIH HHSUnited StatesR01 AG014358AGNIA NIH HHSUnited StatesR01 CA098438-03CANCI NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., Extramural
1098-10043132010MarHuman mutationHum MutatCharacterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.E1200E1240E1200-4010.1002/humu.21202BRCA1 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.(c) 2010 Wiley-Liss, Inc.BorgAkeADepartment of Oncology, Clinical Sciences, Lund University, Lund, Sweden. ake.borg@med.lu.seHaileRobert WRWMaloneKathleen EKECapanuMarinelaMDiepAhnATörngrenThereseTTeraokaSharonSBeggColin BCBThomasDuncan CDCConcannonPatrickPMellemkjaerLeneLBernsteinLeslieLTellhedLinaLXueShanyanSOlsonEric RERLiangXiaolinXDolleJessicaJBørresen-DaleAnne-LiseALBernsteinJonine LJLengR01 CA131010CANCI NIH HHSUnited StatesR01 CA097397CANCI NIH HHSUnited StatesR01 CA097397-05CANCI NIH HHSUnited StatesR01 CA131010-02CANCI NIH HHSUnited StatesR01 CA098438CANCI NIH HHSUnited StatesCA097397CANCI NIH HHSUnited StatesR01 CA129639CANCI NIH HHSUnited StatesCA098438CANCI NIH HHSUnited StatesCA131010CANCI NIH HHSUnited StatesR01 AG014358AGNIA NIH HHSUnited StatesR01 CA098438-03CANCI NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., Extramural