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

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 YangGeorgia 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, ENIGMA consortium

11 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftGenetics in medicine : official journal of the American College of Medical Genetics
Vol/bind24
Udgave nummer1
Sider (fra-til)119-129
Antal sider11
ISSN1098-3600
DOI
StatusUdgivet - jan. 2022

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