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 Pg Vreeswijk; Linda Am Janssen; Åke 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 Søkilde Pedersen; Sandrine M Caputo; Fergus Couch; Emily J Hallberg; Ans Mw van den Ouweland; Margriet J Collée; Erik Teugels; Muriel A Adank; Rob B van der Luijt; Arjen R Mensenkamp; Jan C Oosterwijk; Marinus J Blok; Nicolas Janin; Kathleen Bm Claes; Kathy Tucker; Valeria Viassolo; Amanda Ewart Toland; Diana E Eccles; Peter Devilee; Christie J Van Asperen; Amanda B Spurdle; David E Goldgar; Encarna Gómez García

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 Pg Vreeswijk, Linda Am Janssen, Åke 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 Søkilde Pedersen, Sandrine M Caputo, Fergus CouchEmily J Hallberg, Ans Mw van den Ouweland, Margriet J Collée, Erik Teugels, Muriel A Adank, Rob B van der Luijt, Arjen R Mensenkamp, Jan C Oosterwijk, Marinus J Blok, Nicolas Janin, Kathleen Bm Claes, Kathy Tucker, Valeria Viassolo, Amanda Ewart Toland, Diana E Eccles, Peter Devilee, Christie J Van Asperen, Amanda B Spurdle, David E Goldgar, Encarna Gómez García

Department of Clinical Medicine

27 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medical Genetics
Volume	55
Issue number	1
Pages (from-to)	15-20
ISSN	0022-2593
DOIs	https://doi.org/10.1136/jmedgenet-2017-104560
Publication status	Published - Jan 2018

Keywords

BRCA1 Protein/genetics
Breast Neoplasms/genetics
Chromosome Segregation
Female
Genetic Predisposition to Disease
Humans
Mutation/genetics
Ovarian Neoplasms/genetics
Risk Factors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1136/jmedgenet-2017-104560

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Moghadasi, S., Meeks, H. D., Vreeswijk, M. P., Janssen, L. A., Borg, Å., 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., ... García, 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

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 Pg et al.

In: Journal of Medical Genetics, Vol. 55, No. 1, 01.2018, p. 15-20.

Research output: Contribution to journal › Journal article › Research › peer-review

Moghadasi, S, Meeks, HD, Vreeswijk, MP, Janssen, LA, Borg, Å, 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, AM, Collée, MJ, Teugels, E, Adank, MA, van der Luijt, RB, Mensenkamp, AR, Oosterwijk, JC, Blok, MJ, Janin, N, Claes, KB, Tucker, K, Viassolo, V, Toland, AE, Eccles, DE, Devilee, P, Van Asperen, CJ, Spurdle, AB, Goldgar, DE & García, 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

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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: 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.",

keywords = "BRCA1 Protein/genetics, Breast Neoplasms/genetics, Chromosome Segregation, Female, Genetic Predisposition to Disease, Humans, Mutation/genetics, Ovarian Neoplasms/genetics, Risk Factors",

author = "Setareh Moghadasi and Meeks, {Huong D} and Vreeswijk, {Maaike Pg} and Janssen, {Linda Am} and {\AA}ke 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 S{\o}kilde} and Caputo, {Sandrine M} and Fergus Couch and Hallberg, {Emily J} and {van den Ouweland}, {Ans Mw} and Coll{\'e}e, {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 Bm} 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 Garc{\'i}a, {Encarna G{\'o}mez}",

note = "{\textcopyright} Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.",

year = "2018",

month = jan,

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

language = "English",

volume = "55",

pages = "15--20",

journal = "Journal of Medical Genetics",

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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 Pg

AU - Janssen, Linda Am

AU - Borg, Åke

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 Søkilde

AU - Caputo, Sandrine M

AU - Couch, Fergus

AU - Hallberg, Emily J

AU - van den Ouweland, Ans Mw

AU - Collée, 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 Bm

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 - García, Encarna Gómez

PY - 2018/1

Y1 - 2018/1

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: 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.

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: 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.

KW - BRCA1 Protein/genetics

KW - Breast Neoplasms/genetics

KW - Chromosome Segregation

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Mutation/genetics

KW - Ovarian Neoplasms/genetics

KW - Risk Factors

U2 - 10.1136/jmedgenet-2017-104560

DO - 10.1136/jmedgenet-2017-104560

M3 - Journal 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 -

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

Keywords

UN SDGs

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