Li, Hongyan, Engel, Christoph ORCID: 0000-0002-7247-282X, de la Hoya, Miguel, Peterlongo, Paolo ORCID: 0000-0001-6951-6855, Yannoukakos, Drakoulis, Livraghi, Luca ORCID: 0000-0002-9119-6277, Radice, Paolo, Thomassen, Mads, Hansen, Thomas V. O., Gerdes, Anne-Marie, Nielsen, Henriette R., Caputo, Sandrine M. ORCID: 0000-0001-5338-9388, Zambelli, Alberto ORCID: 0000-0002-1374-1831, Borg, Ake, Solano, Angela, Thomas, Abigail, Parsons, Michael T., Antoniou, Antonis C., Leslie, Goska, Yang, Xin, Chenevix-Trench, Georgia, Caldes, Trinidad, Kwong, Ava, Pedersen, Inge Sokilde, Lautrup, Charlotte K., John, Esther M., Terry, Mary Beth ORCID: 0000-0002-4106-5033, Hopper, John L., Southey, Melissa C., Andrulis, Irene L., Tischkowitz, Marc, Janavicius, Ramunas, Boonen, Susanne E. ORCID: 0000-0002-7824-2080, Kroeldrup, Lone, Varesco, Liliana, Hamann, Ute, Vega, Ana, Palmero, Edenir, I, Garber, Judy, Montagna, Marco, Van Asperen, Christi J., Foretova, Lenka, Greene, Mark H., Selkirk, Tina, Moller, Pal, Toland, Amanda E., Domchek, Susan M., James, Paul A., Thorne, Heather, Eccles, Diana M., Nielsen, Sarah M., Manoukian, Siranoush, Pasini, Barbara ORCID: 0000-0002-4373-1212, Caligo, Maria A., Lazaro, Conxi, Kirk, Judy, Wappenschmidt, Barbara, Spurdle, Amanda B., Couch, Fergus J., Schmutzler, Rita and Goldgar, David E. (2022). Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants. Genet. Med., 24 (1). S. 119 - 130. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1530-0366

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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. (C) 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Li, HongyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, ChristophUNSPECIFIEDorcid.org/0000-0002-7247-282XUNSPECIFIED
de la Hoya, MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peterlongo, PaoloUNSPECIFIEDorcid.org/0000-0001-6951-6855UNSPECIFIED
Yannoukakos, DrakoulisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Livraghi, LucaUNSPECIFIEDorcid.org/0000-0002-9119-6277UNSPECIFIED
Radice, PaoloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomassen, MadsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Thomas V. O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerdes, Anne-MarieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Henriette R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caputo, Sandrine M.UNSPECIFIEDorcid.org/0000-0001-5338-9388UNSPECIFIED
Zambelli, AlbertoUNSPECIFIEDorcid.org/0000-0002-1374-1831UNSPECIFIED
Borg, AkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solano, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, AbigailUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parsons, Michael T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Antoniou, Antonis C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leslie, GoskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yang, XinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chenevix-Trench, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldes, TrinidadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwong, AvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Inge SokildeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lautrup, Charlotte K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
John, Esther M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Terry, Mary BethUNSPECIFIEDorcid.org/0000-0002-4106-5033UNSPECIFIED
Hopper, John L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Southey, Melissa C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrulis, Irene L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tischkowitz, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janavicius, RamunasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boonen, Susanne E.UNSPECIFIEDorcid.org/0000-0002-7824-2080UNSPECIFIED
Kroeldrup, LoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varesco, LilianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hamann, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vega, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palmero, Edenir, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garber, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Montagna, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Asperen, Christi J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foretova, LenkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Greene, Mark H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selkirk, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moller, PalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toland, Amanda E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domchek, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
James, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thorne, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eccles, Diana M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, Sarah M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manoukian, SiranoushUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasini, BarbaraUNSPECIFIEDorcid.org/0000-0002-4373-1212UNSPECIFIED
Caligo, Maria A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lazaro, ConxiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirk, JudyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wappenschmidt, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spurdle, Amanda B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Couch, Fergus J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmutzler, RitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldgar, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699337
DOI: 10.1016/j.gim.2021.08.016
Journal or Publication Title: Genet. Med.
Volume: 24
Number: 1
Page Range: S. 119 - 130
Date: 2022
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
UNKNOWN CLINICAL-SIGNIFICANCE; SEQUENCE VARIANTS; UNCERTAIN SIGNIFICANCE; INTEGRATED EVALUATION; FAMILY-HISTORY; MUTATION; CLASSIFICATION; SUBSTITUTIONS; NETWORK; GENEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69933

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