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The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
Background: we previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. Methods: data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. Results: in this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). Conclusion: our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.
0022-2593
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Moghadasi, Setareh
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Collée, Margriet J.
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Teugels, Erik
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Adank, Muriel A.
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van der Luijt, Rob B.
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Mensenkamp, Arjen R.
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Oosterwijk, Jan C.
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Viassolo, Valeria
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Toland, Amanda Ewart
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Eccles, Diana E.
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Devilee, Peter
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Spurdle, Amanda B.
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Goldgar, David E.
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García, Encarna Gómez
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Moghadasi, Setareh
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Meeks, Huong D.
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Vreeswijk, Maaike P.G.
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Janssen, Linda Am
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Borg, Åke
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Ehrencrona, Hans
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Paulsson-Karlsson, Ylva
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Wappenschmidt, Barbara
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Engel, Christoph
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Gehrig, Andrea
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Arnold, Norbert
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Collée, Margriet J.
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Teugels, Erik
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Adank, Muriel A.
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van der Luijt, Rob B.
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Mensenkamp, Arjen R.
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Janin, Nicolas
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Claes, Kathleen B.M.
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Tucker, Kathy
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Viassolo, Valeria
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Toland, Amanda Ewart
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Eccles, Diana E.
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Devilee, Peter
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Van Asperen, Christie J.
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Spurdle, Amanda B.
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Goldgar, David E.
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García, Encarna Gómez
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Moghadasi, Setareh, Meeks, Huong D., Vreeswijk, Maaike P.G., Janssen, Linda Am, Borg, Åke, Ehrencrona, Hans, Paulsson-Karlsson, Ylva, Wappenschmidt, Barbara, Engel, Christoph, Gehrig, Andrea, Arnold, Norbert, Hansen, Thomas Van Overeem, Thomassen, Mads, Jensen, Uffe Birk, Kruse, Torben A., Ejlertsen, Bent, Gerdes, Anne-Marie, Pedersen, Inge Søkilde, Caputo, Sandrine M., Couch, Fergus, Hallberg, Emily J., van den Ouweland, Ans M.W., Collée, Margriet J., Teugels, Erik, Adank, Muriel A., van der Luijt, Rob B., Mensenkamp, Arjen R., Oosterwijk, Jan C., Blok, Marinus J., Janin, Nicolas, Claes, Kathleen B.M., Tucker, Kathy, Viassolo, Valeria, Toland, Amanda Ewart, Eccles, Diana E., Devilee, Peter, Van Asperen, Christie J., Spurdle, Amanda B., Goldgar, David E. and García, Encarna Gómez (2017) The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. Journal of Medical Genetics, 1-7. (doi:10.1136/jmedgenet-2017-104560).

Record type: Article

Abstract

Background: we previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. Methods: data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. Results: in this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). Conclusion: our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.

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Accepted/In Press date: 17 April 2017
e-pub ahead of print date: 10 May 2017

Identifiers

Local EPrints ID: 413866
URI: http://eprints.soton.ac.uk/id/eprint/413866
DOI: doi:10.1136/jmedgenet-2017-104560
ISSN: 0022-2593
PURE UUID: 85023979-6e67-42a1-929b-7036bd03cdcd
ORCID for Diana E. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 08 Sep 2017 16:30
Last modified: 16 Mar 2024 02:39

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Contributors

Author: Setareh Moghadasi
Author: Huong D. Meeks
Author: Maaike P.G. Vreeswijk
Author: Linda Am Janssen
Author: Åke Borg
Author: Hans Ehrencrona
Author: Ylva Paulsson-Karlsson
Author: Barbara Wappenschmidt
Author: Christoph Engel
Author: Andrea Gehrig
Author: Norbert Arnold
Author: Thomas Van Overeem Hansen
Author: Mads Thomassen
Author: Uffe Birk Jensen
Author: Torben A. Kruse
Author: Bent Ejlertsen
Author: Anne-Marie Gerdes
Author: Inge Søkilde Pedersen
Author: Sandrine M. Caputo
Author: Fergus Couch
Author: Emily J. Hallberg
Author: Ans M.W. van den Ouweland
Author: Margriet J. Collée
Author: Erik Teugels
Author: Muriel A. Adank
Author: Rob B. van der Luijt
Author: Arjen R. Mensenkamp
Author: Jan C. Oosterwijk
Author: Marinus J. Blok
Author: Nicolas Janin
Author: Kathleen B.M. Claes
Author: Kathy Tucker
Author: Valeria Viassolo
Author: Amanda Ewart Toland
Author: Diana E. Eccles ORCID iD
Author: Peter Devilee
Author: Christie J. Van Asperen
Author: Amanda B. Spurdle
Author: David E. Goldgar
Author: Encarna Gómez García

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