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

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

doi:10.1136/jmedgenet-2017-104560

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

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 O ur 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 salpingooophorectomy should be considered based on family history.

Original language	English
Pages (from-to)	15-20
Number of pages	6
Journal	Journal of Medical Genetics
Volume	55
Issue number	1
DOIs	https://doi.org/10.1136/jmedgenet-2017-104560
Publication status	Published - 1 Jan 2018

Keywords

SEQUENCE VARIANTS
CLASSIFICATION
MUTATIONS

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10.1136/jmedgenet-2017-104560

Cite this

Moghadasi, S., Meeks, H. D., Vreeswijk, M. P. G., Janssen, L. A. M., Borg, A., Ehrencrona, H., Paulsson-Karlsson, Y., Wappenschmidt, B., Engel, C., Gehrig, A., Arnold, N., Hansen, T. V. O., Thomassen, M., Jensen, U. B., Kruse, T. A., Ejlertsen, B., Gerdes, A.-M., Pedersen, I. S., Caputo, S. M., ... Garcia, E. G. (2018). 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, 55(1), 15-20. https://doi.org/10.1136/jmedgenet-2017-104560

@article{6daabb4e9509491cbad855dc112c1c34,

title = "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",

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 O ur 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 salpingooophorectomy should be considered based on family history.",

keywords = "SEQUENCE VARIANTS, CLASSIFICATION, MUTATIONS",

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

year = "2018",

month = jan,

day = "1",

doi = "10.1136/jmedgenet-2017-104560",

language = "English",

volume = "55",

pages = "15--20",

journal = "Journal of Medical Genetics",

issn = "0022-2593",

publisher = "BMJ Publishing Group",

number = "1",

}

Moghadasi, S, Meeks, HD, Vreeswijk, MPG, Janssen, LAM, Borg, A, Ehrencrona, H, Paulsson-Karlsson, Y, Wappenschmidt, B, Engel, C, Gehrig, A, Arnold, N, Hansen, TVO, Thomassen, M, Jensen, UB, Kruse, TA, Ejlertsen, B, Gerdes, A-M, Pedersen, IS, Caputo, SM, Couch, F, Hallberg, EJ, van den Ouweland, AMW, Collee, MJ, Teugels, E, Adank, MA, van der Luijt, RB, Mensenkamp, AR, Oosterwijk, JC, Blok, MJ, Janin, N, Claes, KBM, Tucker, K, Viassolo, V, Toland, AE, Eccles, DE, Devilee, P, Van Asperen, CJ, Spurdle, AB, Goldgar, DE & Garcia, EG 2018, '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, vol. 55, no. 1, pp. 15-20. https://doi.org/10.1136/jmedgenet-2017-104560

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. / Moghadasi, Setareh; Meeks, Huong D.; Vreeswijk, Maaike P. G. et al.
In: Journal of Medical Genetics, Vol. 55, No. 1, 01.01.2018, p. 15-20.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - The BRCA1 c. 5096G > A p.Arg1699Gln (R1699Q) intermediate risk variant

T2 - breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

AU - Moghadasi, Setareh

AU - Meeks, Huong D.

AU - Vreeswijk, Maaike P. G.

AU - Janssen, Linda A. M.

AU - Borg, Ake

AU - Ehrencrona, Hans

AU - Paulsson-Karlsson, Ylva

AU - Wappenschmidt, Barbara

AU - Engel, Christoph

AU - Gehrig, Andrea

AU - Arnold, Norbert

AU - Hansen, Thomas Van Overeem

AU - Thomassen, Mads

AU - Jensen, Uffe Birk

AU - Kruse, Torben A.

AU - Ejlertsen, Bent

AU - Gerdes, Anne-Marie

AU - Pedersen, Inge Sokilde

AU - Caputo, Sandrine M.

AU - Couch, Fergus

AU - Hallberg, Emily J.

AU - van den Ouweland, Ans M. W.

AU - Collee, Margriet J.

AU - Teugels, Erik

AU - Adank, Muriel A.

AU - van der Luijt, Rob B.

AU - Mensenkamp, Arjen R.

AU - Oosterwijk, Jan C.

AU - Blok, Marinus J.

AU - Janin, Nicolas

AU - Claes, Kathleen B. M.

AU - Tucker, Kathy

AU - Viassolo, Valeria

AU - Toland, Amanda Ewart

AU - Eccles, Diana E.

AU - Devilee, Peter

AU - Van Asperen, Christie J.

AU - Spurdle, Amanda B.

AU - Goldgar, David E.

AU - Garcia, Encarna Gomez

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 O ur 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 salpingooophorectomy should be considered based on family history.

AB - 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 O ur 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 salpingooophorectomy should be considered based on family history.

KW - SEQUENCE VARIANTS

KW - CLASSIFICATION

KW - MUTATIONS

U2 - 10.1136/jmedgenet-2017-104560

DO - 10.1136/jmedgenet-2017-104560

M3 - Article

C2 - 28490613

SN - 0022-2593

VL - 55

SP - 15

EP - 20

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

IS - 1

ER -