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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
BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk
BACKGROUND: 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.

METHODS: 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).

RESULTS: 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%.

CONCLUSIONS: 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.
0022-2593
525-532
Spurdle, A.B.
79a08784-9f45-4c4f-9bd2-cf1db78f2cda
Whiley, P.J.
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Thompson, B.
40ffb6b8-0f16-43b1-b5e2-38b5edf3b5ce
Feng, B.
81ff78d5-a041-4f84-84e6-8b1302b9e343
Healey, S.
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Brown, M.A.
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Pettigrew, C.
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Van Asperen, C.J.
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Ausems, M.G.E.M.
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Kattentidt-Mouravieva, A.A.
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van den Ouweland, A.M.W.
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Belgium UV Consortium, D.
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Lindblom, A.
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Pigg, M.H.
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Schmutzler, R.K.
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Engel, C.
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Meindl, A.
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Caputo, S.
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Sinilnikova, O.M.
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Lidereau, R.
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Couch, F.J.
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Guidugli, L.
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Hansen, T.v.O.
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Thomassen, M.
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Eccles, D.M.
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Tucker, K.
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Benitez, J.
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Domchek, S.M.
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Toland, A.E.
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Van Rensburg, E.J.
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Wappenschmidt, B.
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Borg, A.
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Vreeswijk, M.P.G.
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Goldgar, D.E.
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Spurdle, A.B.
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Whiley, P.J.
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Thompson, B.
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Feng, B.
81ff78d5-a041-4f84-84e6-8b1302b9e343
Healey, S.
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Brown, M.A.
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Pettigrew, C.
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Van Asperen, C.J.
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Ausems, M.G.E.M.
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Kattentidt-Mouravieva, A.A.
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van den Ouweland, A.M.W.
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Belgium UV Consortium, D.
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Lindblom, A.
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Pigg, M.H.
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Schmutzler, R.K.
70d436d3-82ba-45dd-baaf-b97b8dda961f
Engel, C.
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Meindl, A.
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Caputo, S.
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Sinilnikova, O.M.
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Lidereau, R.
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Couch, F.J.
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Guidugli, L.
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Hansen, T.v.O.
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Thomassen, M.
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Eccles, D.M.
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Tucker, K.
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Benitez, J.
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Domchek, S.M.
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Toland, A.E.
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Van Rensburg, E.J.
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Wappenschmidt, B.
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Borg, A.
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Vreeswijk, M.P.G.
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Goldgar, D.E.
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Spurdle, A.B., Whiley, P.J., Thompson, B., Feng, B., Healey, S., Brown, M.A., Pettigrew, C., Van Asperen, C.J., Ausems, M.G.E.M., Kattentidt-Mouravieva, A.A., van den Ouweland, A.M.W., Belgium UV Consortium, D., Lindblom, A., Pigg, M.H., Schmutzler, R.K., Engel, C., Meindl, A., Caputo, S., Sinilnikova, O.M., Lidereau, R., Couch, F.J., Guidugli, L., Hansen, T.v.O., Thomassen, M., Eccles, D.M., Tucker, K., Benitez, J., Domchek, S.M., Toland, A.E., Van Rensburg, E.J., Wappenschmidt, B., Borg, A., Vreeswijk, M.P.G. and Goldgar, D.E. (2012) BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. Journal of Medical Genetics, 49 (8), 525-532. (doi:10.1136/jmedgenet-2012-101037). (PMID:22889855)

Record type: Article

Abstract

BACKGROUND: 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.

METHODS: 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).

RESULTS: 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%.

CONCLUSIONS: 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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Published date: August 2012
Organisations: Cancer Sciences

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Local EPrints ID: 352310
URI: https://eprints.soton.ac.uk/id/eprint/352310
ISSN: 0022-2593
PURE UUID: 0d1b81db-5562-4435-be84-3f138cbd42c5

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Date deposited: 09 May 2013 11:35
Last modified: 18 Jul 2017 04:15

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Contributors

Author: A.B. Spurdle
Author: P.J. Whiley
Author: B. Thompson
Author: B. Feng
Author: S. Healey
Author: M.A. Brown
Author: C. Pettigrew
Author: C.J. Van Asperen
Author: M.G.E.M. Ausems
Author: A.A. Kattentidt-Mouravieva
Author: A.M.W. van den Ouweland
Author: D. Belgium UV Consortium
Author: A. Lindblom
Author: M.H. Pigg
Author: R.K. Schmutzler
Author: C. Engel
Author: A. Meindl
Author: S. Caputo
Author: O.M. Sinilnikova
Author: R. Lidereau
Author: F.J. Couch
Author: L. Guidugli
Author: T.v.O. Hansen
Author: M. Thomassen
Author: D.M. Eccles
Author: K. Tucker
Author: J. Benitez
Author: S.M. Domchek
Author: A.E. Toland
Author: E.J. Van Rensburg
Author: B. Wappenschmidt
Author: A. Borg
Author: M.P.G. Vreeswijk
Author: D.E. Goldgar

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