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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
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Genetics in Medicine |
Volume | 24 |
Issue number | 1 |
Pages (from-to) | 119-129 |
Number of pages | 11 |
ISSN | 1098-3600 |
DOIs | |
Publication status | Published - Jan 2022 |
Research output: Contribution to journal › Comment/debate › Communication