Open AccessExon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer
Author(s) -
Ryu JinSun,
Lee HyeYoung,
Cho Eun Hae,
Yoon KyongAh,
Kim MinKyeong,
Joo Jungnam,
Lee EunSook,
Kang HanSung,
Lee Seeyoun,
Lee Dong Ock,
Lim Myong Cheol,
Kong SunYoung
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14600
Subject(s) - chek2 , palb2 , exon , mutyh , genetics , breast cancer , mlh1 , ovarian cancer , rna splicing , biology , cdkn2a , gene , germline mutation , cancer , cancer research , dna mismatch repair , mutation , colorectal cancer , rna
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.