Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants.
BRCA1
BRCA2
Cancer risks
Missense variants
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
14
05
2021
revised:
22
07
2021
accepted:
25
08
2021
pubmed:
16
12
2021
medline:
23
3
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
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. 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. 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. These results have important implications for the counseling of at-risk women who harbor missense PVs in the BRCA1/2 genes.
Identifiants
pubmed: 34906479
pii: S1098-3600(21)01130-8
doi: 10.1016/j.gim.2021.08.016
pmc: PMC10170303
mid: NIHMS1858554
pii:
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119-129Subventions
Organisme : NCI NIH HHS
ID : R01 CA225662
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA164920
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA116167
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA116201
Pays : United States
Organisme : Cancer Research UK
ID : C12292/A20861
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R35 CA253187
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of Interest F.J.C. has received consulting fees from Astrazeneca. A.S. has received consulting fees from Pfizer and Astra Zeneca. T.V.O.H. has received honoraria from Pfizer. All other authors declare no conflicts of interest.
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