Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer.
BRCA2
ES cell-based assay
breast cancer
functional evaluation
molecular dynamic analysis
variants of uncertain clinical significance (VUS)
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
29
01
2020
revised:
29
09
2020
accepted:
28
11
2020
pubmed:
15
12
2020
medline:
1
4
2022
entrez:
14
12
2020
Statut:
ppublish
Résumé
The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.
Identifiants
pubmed: 33314489
doi: 10.1002/humu.24154
pmc: PMC7919386
mid: NIHMS1654748
doi:
Substances chimiques
BRCA1 Protein
0
BRCA2 Protein
0
BRCA2 protein, human
0
BRCA2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
200-212Subventions
Organisme : Wellcome Trust
ID : 203477/Z/16/Z
Pays : United Kingdom
Organisme : Biomedical Research Council
ID : 05/1/21/19/425
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011181
Pays : United States
Organisme : Wellcome Trust
ID : V203477/Z/16/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
Published 2020. This article is a U.S. Goverment work and is in the public domain in the USA.
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