BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk.
BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk.
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DOI：
10.1136/jmedgenet-2012-101037
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发表时间：
2012-08
影响因子：
4
通讯作者：
ENIGMA Consortium
中科院分区：
文献类型：
--
作者：
Spurdle AB;Whiley PJ;Thompson B;Feng B;Healey S;Brown MA;Pettigrew C;kConFab;Van Asperen CJ;Ausems MG;Kattentidt-Mouravieva AA;van den Ouweland AM;Dutch Belgium UV Consortium;Lindblom A;Pigg MH;Schmutzler RK;Engel C;Meindl A;German Consortium of Hereditary Breast and Ovarian Cancer;Caputo S;Sinilnikova OM;Lidereau R;French COVAR group collaborators;Couch FJ;Guidugli L;Hansen Tv;Thomassen M;Eccles DM;Tucker K;Benitez J;Domchek SM;Toland AE;Van Rensburg EJ;Wappenschmidt B;Borg Å;Vreeswijk MP;Goldgar DE;ENIGMA Consortium
Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘BRCA1-like’ than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.
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DOI：
10.1186/bcr2919
发表时间：
2011-07-25
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Goldgar DE;Healey S;Dowty JG;Da Silva L;Chen X;Spurdle AB;Terry MB;Daly MJ;Buys SM;Southey MC;Andrulis I;John EM;BCFR;kConFab;Khanna KK;Hopper JL;Oefner PJ;Lakhani S;Chenevix-Trench G
通讯作者：
Chenevix-Trench G
影响因子：
9.8
作者：
Easton, Douglas F.;Deffenbaugh, Amie M.;Goldgar, David E.
通讯作者：
Goldgar, David E.
DOI：
10.1186/bcr2223
发表时间：
2009
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Gómez García EB;Oosterwijk JC;Timmermans M;van Asperen CJ;Hogervorst FB;Hoogerbrugge N;Oldenburg R;Verhoef S;Dommering CJ;Ausems MG;van Os TA;van der Hout AH;Ligtenberg M;van den Ouweland A;van der Luijt RB;Wijnen JT;Gille JJ;Lindsey PJ;Devilee P;Blok MJ;Vreeswijk MP
通讯作者：
Vreeswijk MP
影响因子：
9.8
作者：
Goldgar, DE;Easton, DF;Couch, FJ
通讯作者：
Couch, FJ
影响因子：
3.5
作者：
Cox, David G.;Simard, Jacques;Sinilnikova, Olga M.
通讯作者：
Sinilnikova, Olga M.