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.
|Number of pages||14|
|Publication status||Published - 2020 Oct 1|
Bibliographical noteFunding Information:
This work was supported by grants from the National Cancer Center [grant number NCC‐1611161] and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [grant number 2018R1A6A3A01012838]. This work was also supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean government (MSIT) [grant number 2020R1A2C2010566]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank the researchers at the Center for Breast Cancer and Gynecologic Cancer of the National Cancer Center (Republic of Korea) for helping collect patient samples and clinical data.
© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
All Science Journal Classification (ASJC) codes
- Cancer Research