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Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants
Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

BRCA1, BRCA2, Cancer risks, Missense variants
1098-3600
119-129
Li, Hongyan
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Engel, Christoph
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de la Hoya, Miguel
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Peterlongo, Paolo
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Yannoukakos, Drakoulis
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Livraghi, Luca
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Radice, Paolo
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Thomassen, Mads
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Hansen, Thomas V.O.
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Gerdes, Anne Marie
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Caputo, Sandrine M.
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Thomas, Abigail
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Parsons, Michael T.
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Leslie, Goska
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Yang, Xin
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Pedersen, Inge Søkilde
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Lautrup, Charlotte K.
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John, Esther M.
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Terry, Mary Beth
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Hopper, John L.
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Southey, Melissa C.
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Andrulis, Irene L.
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Tischkowitz, Marc
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Janavicius, Ramunas
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Boonen, Susanne E.
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Kroeldrup, Lone
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Varesco, Liliana
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Hamann, Ute
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Vega, Ana
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Palmero, Edenir I.
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Garber, Judy
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Montagna, Marco
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Van Asperen, Christi J.
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Foretova, Lenka
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Greene, Mark H.
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Selkirk, Tina
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Moller, Pal
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Toland, Amanda E.
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Domchek, Susan M.
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James, Paul A.
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Thorne, Heather
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Eccles, Diana M.
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Goldgar, David E.
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ENIGMA Consortium
CIMBA Consortium
Li, Hongyan
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Engel, Christoph
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de la Hoya, Miguel
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Peterlongo, Paolo
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Yannoukakos, Drakoulis
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Livraghi, Luca
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Radice, Paolo
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Thomassen, Mads
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Hansen, Thomas V.O.
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Gerdes, Anne Marie
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Nielsen, Henriette R.
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Caputo, Sandrine M.
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Zambelli, Alberto
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Borg, Ake
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Solano, Angela
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Thomas, Abigail
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Parsons, Michael T.
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Antoniou, Antonis C.
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Leslie, Goska
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Yang, Xin
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Chenevix-Trench, Georgia
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Caldes, Trinidad
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Kwong, Ava
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Pedersen, Inge Søkilde
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Lautrup, Charlotte K.
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John, Esther M.
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Terry, Mary Beth
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Hopper, John L.
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Southey, Melissa C.
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Andrulis, Irene L.
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Tischkowitz, Marc
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Janavicius, Ramunas
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Boonen, Susanne E.
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Kroeldrup, Lone
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Varesco, Liliana
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Hamann, Ute
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Vega, Ana
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Palmero, Edenir I.
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Garber, Judy
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Montagna, Marco
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Van Asperen, Christi J.
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Foretova, Lenka
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Greene, Mark H.
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Selkirk, Tina
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Moller, Pal
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Toland, Amanda E.
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Domchek, Susan M.
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James, Paul A.
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Thorne, Heather
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Eccles, Diana M.
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Goldgar, David E.
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Li, Hongyan, Engel, Christoph, de la Hoya, Miguel, Peterlongo, Paolo, Yannoukakos, Drakoulis, Livraghi, Luca, Eccles, Diana M. and Goldgar, David E. , ENIGMA Consortium and CIMBA Consortium (2022) Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. Genetics in Medicine, 24 (1), 119-129. (doi:10.1016/j.gim.2021.08.016).

Record type: Article

Abstract

Purpose: Germline genetic testing for BRCA1 and BRCA2 variants has been a part of clinical practice for >2 decades. However, no studies have compared the cancer risks associated with missense pathogenic variants (PVs) with those associated with protein truncating (PTC) variants. Methods: We collected 582 informative pedigrees segregating 1 of 28 missense PVs in BRCA1 and 153 pedigrees segregating 1 of 12 missense PVs in BRCA2. We analyzed 324 pedigrees with PTC variants in BRCA1 and 214 pedigrees with PTC variants in BRCA2. Cancer risks were estimated using modified segregation analysis. Results: Estimated breast cancer risks were markedly lower for women aged >50 years carrying BRCA1 missense PVs than for the women carrying BRCA1 PTC variants (hazard ratio [HR] = 3.9 [2.4-6.2] for PVs vs 12.8 [5.7-28.7] for PTC variants; P =.01), particularly for missense PVs in the BRCA1 C-terminal domain (HR = 2.8 [1.4-5.6]; P =.005). In case of BRCA2, for women aged >50 years, the HR was 3.9 (2.0-7.2) for those heterozygous for missense PVs compared with 7.0 (3.3-14.7) for those harboring PTC variants. BRCA1 p.[Cys64Arg] and BRCA2 p.[Trp2626Cys] were associated with particularly low risks of breast cancer compared with other PVs. Conclusion: These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.

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GIM_2021_Li_Goldgar - Accepted Manuscript
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Accepted/In Press date: 25 August 2021
e-pub ahead of print date: 30 November 2021
Published date: 5 January 2022
Keywords: BRCA1, BRCA2, Cancer risks, Missense variants

Identifiers

Local EPrints ID: 454437
URI: http://eprints.soton.ac.uk/id/eprint/454437
ISSN: 1098-3600
PURE UUID: bc29f47d-b475-402b-983c-569206f7ac36
ORCID for Diana M. Eccles: ORCID iD orcid.org/0000-0002-9935-3169

Catalogue record

Date deposited: 09 Feb 2022 17:39
Last modified: 25 Jun 2022 01:33

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Contributors

Author: Hongyan Li
Author: Christoph Engel
Author: Miguel de la Hoya
Author: Paolo Peterlongo
Author: Drakoulis Yannoukakos
Author: Luca Livraghi
Author: Paolo Radice
Author: Mads Thomassen
Author: Thomas V.O. Hansen
Author: Anne Marie Gerdes
Author: Henriette R. Nielsen
Author: Sandrine M. Caputo
Author: Alberto Zambelli
Author: Ake Borg
Author: Angela Solano
Author: Abigail Thomas
Author: Michael T. Parsons
Author: Antonis C. Antoniou
Author: Goska Leslie
Author: Xin Yang
Author: Georgia Chenevix-Trench
Author: Trinidad Caldes
Author: Ava Kwong
Author: Inge Søkilde Pedersen
Author: Charlotte K. Lautrup
Author: Esther M. John
Author: Mary Beth Terry
Author: John L. Hopper
Author: Melissa C. Southey
Author: Irene L. Andrulis
Author: Marc Tischkowitz
Author: Ramunas Janavicius
Author: Susanne E. Boonen
Author: Lone Kroeldrup
Author: Liliana Varesco
Author: Ute Hamann
Author: Ana Vega
Author: Edenir I. Palmero
Author: Judy Garber
Author: Marco Montagna
Author: Christi J. Van Asperen
Author: Lenka Foretova
Author: Mark H. Greene
Author: Tina Selkirk
Author: Pal Moller
Author: Amanda E. Toland
Author: Susan M. Domchek
Author: Paul A. James
Author: Heather Thorne
Author: Diana M. Eccles ORCID iD
Author: David E. Goldgar
Corporate Author: ENIGMA Consortium
Corporate Author: CIMBA Consortium

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