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

Li, H.Y.; Engel, C.; Hoya, M. de la; Peterlongo, P.; Yannoukakos, D.; Livraghi, L.; Radice, P.; Thomassen, M.; Hansen, T.V.O.; Gerdes, A.M.; Nielsen, H.R.; Caputo, S.M.; Zambelli, A.; Borg, A.; Solano, A.; Thomas, A.; Parsons, M.T.; Antoniou, A.C.; Leslie, G.; Yang, X.; Chenevix-Trench, G.; Caldes, T.; Kwong, A.; Pedersen, I.S.; Lautrup, C.K.; John, E.M.; Terry, M.B.; Hopper, J.L.; Southey, M.C.; Andrulis, I.L.; Tischkowitz, M.; Janavicius, R.; Boonen, S.E.; Kroeldrup, L.; Varesco, L.; Hamann, U.; Vega, A.; Palmero, E.I.; Garber, J.; Montagna, M.; Asperen, C.J. van; Foretova, L.; Greene, M.H.; Selkirk, T.; Moller, P.; Toland, A.E.; Domchek, S.M.; James, P.A.; Thorne, H.; Eccles, D.M.; Nielsen, S.M.; Manoukian, S.; Pasini, B.; Caligo, M.A.; Lazaro, C.; Kirk, J.; Wappenschmidt, B.; Spurdle, A.B.; Couch, F.J.; Schmutzler, R.; Goldgar, D.E.; ENIGMA Consortium; CIMBA Consortium

doi:doi:10.1016/j.gim.2021.08.016

Persistent URL of this record https://hdl.handle.net/1887/3563134

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Medicine / Leiden University Medical Centre (LUMC)

Li, H.Y.; Engel, C.; Hoya, M. de la; Peterlongo, P.; Yannoukakos, D.; Livraghi, L.; ... ; 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

Article / Letter to editor

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...Show morePurpose: 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.Show less