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Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant

Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomen...

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Autores principales: Li, Jun, Wang, Ping, Zhang, Cuiyun, Han, Sile, Xiao, Han, Liu, Zhiyuan, Wang, Xiaoyan, Liu, Weiling, Wei, Bing, Ma, Jie, Li, Hongle, Guo, Yongjun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789006/
https://www.ncbi.nlm.nih.gov/pubmed/35087763
http://dx.doi.org/10.3389/fonc.2021.812656
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author Li, Jun
Wang, Ping
Zhang, Cuiyun
Han, Sile
Xiao, Han
Liu, Zhiyuan
Wang, Xiaoyan
Liu, Weiling
Wei, Bing
Ma, Jie
Li, Hongle
Guo, Yongjun
author_facet Li, Jun
Wang, Ping
Zhang, Cuiyun
Han, Sile
Xiao, Han
Liu, Zhiyuan
Wang, Xiaoyan
Liu, Weiling
Wei, Bing
Ma, Jie
Li, Hongle
Guo, Yongjun
author_sort Li, Jun
collection PubMed
description Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with “conflicting interpretations of its pathogenicity”. Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients’ family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers.
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spelling pubmed-87890062022-01-26 Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant Li, Jun Wang, Ping Zhang, Cuiyun Han, Sile Xiao, Han Liu, Zhiyuan Wang, Xiaoyan Liu, Weiling Wei, Bing Ma, Jie Li, Hongle Guo, Yongjun Front Oncol Oncology Breast cancer gene 1 (BRCA1) and BRCA2 are tumor suppressors involved in DNA damage response and repair. Carriers of germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 have significantly increased lifetime risks of breast cancer, ovarian cancer, and other cancer types; this phenomenon is known as hereditary breast and ovarian cancer (HBOC) syndrome. Accurate interpretation of BRCA1 and BRCA2 variants is important not only for disease management in patients, but also for determining preventative measures for their families. BRCA1:c.132C>T (p.Cys44=) is a synonymous variant recorded in the ClinVar database with “conflicting interpretations of its pathogenicity”. Here, we report our clinical tests in which we identified this variant in two unrelated patients, both of whom developed breast cancer at an early age with ovarian presentation a few years later and had a family history of relevant cancers. Minigene assay showed that this change caused a four-nucleotide loss at the end of exon 3, resulting in a truncated p.Cys44Tyrfs*5 protein. Reverse transcription-polymerase chain reaction identified two fragments (123 and 119 bp) using RNA isolated from patient blood samples, in consistency with the results of the minigene assay. Collectively, we classified BRCA1:c.132C>T (p.Cys44=) as a pathogenic variant, as evidenced by functional studies, RNA analysis, and the patients’ family histories. By analyzing variants recorded in the BRCA Exchange database, we found synonymous changes at the ends of exons could potentially influence splicing; meanwhile, current in silico tools could not predict splicing changes efficiently if the variants were in the middle of an exon, or in the deep intron region. Future studies should attempt to identify variants that influence gene expression and post-transcription modifications to improve our understanding of BRCA1 and BRCA2, as well as their related cancers. Frontiers Media S.A. 2022-01-11 /pmc/articles/PMC8789006/ /pubmed/35087763 http://dx.doi.org/10.3389/fonc.2021.812656 Text en Copyright © 2022 Li, Wang, Zhang, Han, Xiao, Liu, Wang, Liu, Wei, Ma, Li and Guo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Li, Jun
Wang, Ping
Zhang, Cuiyun
Han, Sile
Xiao, Han
Liu, Zhiyuan
Wang, Xiaoyan
Liu, Weiling
Wei, Bing
Ma, Jie
Li, Hongle
Guo, Yongjun
Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title_full Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title_fullStr Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title_full_unstemmed Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title_short Characterization of Synonymous BRCA1:c.132C>T as a Pathogenic Variant
title_sort characterization of synonymous brca1:c.132c>t as a pathogenic variant
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789006/
https://www.ncbi.nlm.nih.gov/pubmed/35087763
http://dx.doi.org/10.3389/fonc.2021.812656
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