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Abstract  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&gt;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.

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer