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

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.

• Authors: Hongyan Li, Christoph Engel, Miguel de la Hoya, Paolo Peterlongo, Drakoulis Yannoukakos, Luca Livraghi, Paolo Radice, Mads Thomassen, Thomas V O Hansen, Anne-Marie Gerdes, Henriette R Nielsen, Sandrine M Caputo, Alberto Zambelli, Ake Borg, Angela Solano, Abigail Thomas, Michael T Parsons, Antonis C Antoniou, Goska Leslie, Xin Yang, Georgia Chenevix-Trench, Trinidad Caldes, Ava Kwong, Inge Søkilde Pedersen, Charlotte K Lautrup, Esther M John, Mary Beth Terry, John L Hopper, Melissa C Southey, Irene L Andrulis, Marc Tischkowitz, Ramunas Janavicius, Susanne E Boonen, Lone Kroeldrup, Liliana Varesco, Ute Hamann, Ana Vega, Edenir I Palmero, Judy Garber, Marco Montagna, Christi J Van Asperen, Lenka Foretova, Mark H Greene, Tina Selkirk, Pal Moller, Amanda E Toland, Susan M Domchek, Paul A James, Heather Thorne, Diana M Eccles, Sarah M Nielsen, Siranoush Manoukian, Barbara Pasini, Maria A Caligo, Conxi Lazaro, Judy Kirk, Barbara Wappenschmidt, Amanda B Spurdle, Fergus J Couch, Rita Schmutzler, David E Goldgar, ENIGMA Consortium, CIMBA Consortium
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 24 Issue 1 Pg. 119-129 (01 2022) ISSN: 1530-0366 [Electronic] United States
• PMID: 34906479 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human

Topics

• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Breast Neoplasms (genetics, pathology)
• Female
• Genes, BRCA1
• Genes, BRCA2
• Genetic Predisposition to Disease
• Genetic Testing (methods)
• Germ-Line Mutation (genetics)
• Humans
• Middle Aged
• Ovarian Neoplasms (genetics)