Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.
Adult
BRCA1 Protein
/ genetics
Breast Neoplasms
/ genetics
Checkpoint Kinase 2
/ genetics
Exons
/ genetics
Fanconi Anemia Complementation Group Proteins
/ genetics
Female
Germ-Line Mutation
/ genetics
Humans
Middle Aged
Mismatch Repair Endonuclease PMS2
/ genetics
Neoplasm Proteins
/ genetics
Ovarian Neoplasms
/ genetics
RNA Helicases
/ genetics
RNA splicing
germline mutation
hereditary breast and ovarian cancer syndrome
next-generation sequencing
pathogenic/likely Pathogenic
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
23
04
2020
revised:
29
07
2020
accepted:
01
08
2020
pubmed:
8
8
2020
medline:
16
12
2020
entrez:
8
8
2020
Statut:
ppublish
Résumé
The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We identified pathogenic and likely pathogenic (P/LP) variants of high-and moderate-risk genes using a 23-gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high- and moderate-penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT-PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in-frame deletion of the BRCA1 C-terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C-as known VUS-indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.
Identifiants
pubmed: 32761968
doi: 10.1111/cas.14600
pmc: PMC7540976
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Fanconi Anemia Complementation Group Proteins
0
Neoplasm Proteins
0
Checkpoint Kinase 2
EC 2.7.1.11
CHEK2 protein, human
EC 2.7.11.1
PMS2 protein, human
EC 3.6.1.-
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
BRIP1 protein, human
EC 3.6.4.13
RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3912-3925Subventions
Organisme : National Cancer Center
ID : NCC-1611161
Pays : Republic of Korea
Organisme : Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education
ID : 2018R1A6A3A01012838
Organisme : National Research Foundation of Korea (NRF) funded by the Korean government (MSIT)
ID : 2020R1A2C2010566
Informations de copyright
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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