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Identification of a Splice Variant (c.5074+3A > C) of BRCA1 by RNA Sequencing and TOPO Cloning

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Abstract
Grading the pathogenicity of BRCA1/2 variants has great clinical importance in patient treatment as well as in the prevention and screening of hereditary breast and ovarian cancer (HBOC). For accurate evaluation, confirming the splicing effect of a possible splice site variant is crucial. We report a significant splicing variant (c.5074+3A>C) in BRCA1 in a patient with recurrent ovarian cancer. Next-generation sequencing (NGS) of BRCA1/2 from patient's peripheral blood identified the variant, which was strongly suspected of being a splicing mutation based on in silico predictions. Direct RNA analysis yielded multiple transcripts, and TOPO cloning of the complementary DNA (cDNA) and Sanger sequencing revealed an aberrant transcript with an insertion of the first 153 bp of intron 17, and another transcript with the 153 bp insertion along with an exon 18 deletion. A premature termination codon was presumed to be formed by the 153 bp partial intron retention common to the two transcripts. Therefore, BRCA1 c.5074+3A>C was classified as a likely pathogenic variant. Our findings show that active use of functional studies of variants suspected of altered splicing are of great help in classifying them.
Author(s)
구현정김대연김지현민원기이우창전사일홍진경안세희장수환
Issued Date
2021
Type
Article
Keyword
hereditary breast and ovarian cancer syndromeBRCA1 geneRNA sequence analysiscloning
DOI
10.3390/genes12060810
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8586
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_b43eb83962ea4bbd8a46af603f7f012a&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,Identification%20of%20a%20Splice%20Variant%20(c.5074%2B3A%20%3E%20C)%20of%20BRCA1%20by%20RNA%20Sequencing%20and%20TOPO%20Cloning&offset=0&pcAvailability=true
Publisher
GENES
Location
미국
Language
영어
ISSN
2073-4425
Citation Volume
12
Citation Number
6
Citation Start Page
0
Citation End Page
0
Appears in Collections:
Medicine > Medicine
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