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.

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

Yang X.;Pasini B.;
2022-01-01

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.
2022
24
1
119
129
https://www.sciencedirect.com/science/article/pii/S1098360021011308?via=ihub
BRCA1; BRCA2; Cancer risks; Missense variants; BRCA1 Protein; BRCA2 Protein; Female; Genes, BRCA1; Genes, BRCA2; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Humans; Middle Aged; Breast Neoplasms; Ovarian Neoplasms
Li H.; Engel C.; de la Hoya M.; 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.; Van Asperen C.J.; 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1863538
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