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; Engel, C; de la Hoya, M; Peterlongo, P; Yannoukakos, D; Livraghi, L; Radice, P; Thomassen, M; Hansen, TVO; Gerdes, AM; Nielsen, HR; Caputo, SM; Zambelli, A; Borg, A; Solano, A; Thomas, A; Parsons, MT; Antoniou, AC; Leslie, G; Yang, X; Chenevix-Trench, G; Caldes, T; Kwong, A; Pedersen, IS; Lautrup, CK; John, EM; Terry, MB; Hopper, JL; Southey, MC; Andrulis, IL; Tischkowitz, M; Janavicius, R; Boonen, SE; Kroeldrup, L; Varesco, L; Hamann, U; Vega, A; Palmero, EI; Garber, J; Montagna, M; van Asperen, CJ; Foretova, L; Greene, MH; Selkirk, T; Moller, P; Toland, AE; Domchek, SM; James, PA; Thorne, H; Eccles, DM; Nielsen, SM; Manoukian, S; Pasini, B; Caligo, MA; Lazaro, C; Kirk, J; Wappenschmidt, B; Spurdle, AB; Couch, FJ; Schmutzler, R; Goldgar, DE; ENIGMA Consortium; CIMBA Consortium

Author(s): Li, H; Engel, C; de la Hoya, M; Peterlongo, P; Yannoukakos, D; Livraghi, L; Radice, P; Thomassen, M; Hansen, TVO; Gerdes, AM; Nielsen, HR; Caputo, SM; Zambelli, A; Borg, A; Solano, A; Thomas, A; Parsons, MT; Antoniou, AC; Leslie, G; Yang, X; Chenevix-Trench, G; Caldes, T; Kwong, A; Pedersen, IS; Lautrup, CK; John, EM; Terry, MB; Hopper, JL; Southey, MC; Andrulis, IL; Tischkowitz, M; Janavicius, R; Boonen, SE; Kroeldrup, L; Varesco, L; Hamann, U; Vega, A; Palmero, EI; Garber, J; Montagna, M; van Asperen, CJ; Foretova, L; Greene, MH; Selkirk, T; Moller, P; Toland, AE; Domchek, SM; James, PA; Thorne, H; Eccles, DM; Nielsen, SM; Manoukian, S; Pasini, B; Caligo, MA; Lazaro, C; Kirk, J; Wappenschmidt, B; Spurdle, AB; Couch, FJ; Schmutzler, R; Goldgar, DE; ENIGMA Consortium; CIMBA Consortium;
Details: Publication Year 2022-01,Volume 24,Issue #1,Page 119-129
Journal Title: Genetics in Medicine
Publication Type: Research 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.
Keywords: 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; Brca1; Brca2; Cancer risks; Missense variants
Department(s): Familial Cancer Centre; Laboratory Research
PubMed ID: 34906479
Publisher's Version: https://doi.org/10.1016/j.gim.2021.08.016
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-17 07:00:15

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