A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect
BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. METHODS: Five female HBOC probands sequ...
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ftpubmed:oai:pubmedcentral.nih.gov:7005661 2023-05-15T17:21:39+02:00 A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect Dawson, Lesa M. Smith, Kerri N. Werdyani, Salem Ndikumana, Robyn Penney, Cindy Wiede, Louisa L. Smith, Kendra L. Pater, Justin A. MacMillan, Andrée Green, Jane Drover, Sheila Young, Terry‐Lynn O’Rielly, Darren D. 2019-11-28 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005661/ http://www.ncbi.nlm.nih.gov/pubmed/31782267 https://doi.org/10.1002/mgg3.1070 en eng John Wiley and Sons Inc. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005661/ http://www.ncbi.nlm.nih.gov/pubmed/31782267 http://dx.doi.org/10.1002/mgg3.1070 © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. CC-BY Original Articles Text 2019 ftpubmed https://doi.org/10.1002/mgg3.1070 2020-02-16T01:30:19Z BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. METHODS: Five female HBOC probands sequenced negative for moderate‐ and high‐risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. RESULTS: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52‐fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease‐associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild‐type relative. Sanger sequencing of tumors from two probands indicates loss‐of‐heterozygosity, suggesting loss of function. CONCLUSION: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re‐classified as pathogenic according to American College of Medical Genetics and Genomics guidelines. Text Newfoundland PubMed Central (PMC) Molecular Genetics & Genomic Medicine 8 2 |
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Original Articles Dawson, Lesa M. Smith, Kerri N. Werdyani, Salem Ndikumana, Robyn Penney, Cindy Wiede, Louisa L. Smith, Kendra L. Pater, Justin A. MacMillan, Andrée Green, Jane Drover, Sheila Young, Terry‐Lynn O’Rielly, Darren D. A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
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Original Articles |
description |
BACKGROUND: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. METHODS: Five female HBOC probands sequenced negative for moderate‐ and high‐risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. RESULTS: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52‐fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease‐associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild‐type relative. Sanger sequencing of tumors from two probands indicates loss‐of‐heterozygosity, suggesting loss of function. CONCLUSION: The RAD51C c.571 + 4A > G variant affects mRNA splicing and should be re‐classified as pathogenic according to American College of Medical Genetics and Genomics guidelines. |
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Text |
author |
Dawson, Lesa M. Smith, Kerri N. Werdyani, Salem Ndikumana, Robyn Penney, Cindy Wiede, Louisa L. Smith, Kendra L. Pater, Justin A. MacMillan, Andrée Green, Jane Drover, Sheila Young, Terry‐Lynn O’Rielly, Darren D. |
author_facet |
Dawson, Lesa M. Smith, Kerri N. Werdyani, Salem Ndikumana, Robyn Penney, Cindy Wiede, Louisa L. Smith, Kendra L. Pater, Justin A. MacMillan, Andrée Green, Jane Drover, Sheila Young, Terry‐Lynn O’Rielly, Darren D. |
author_sort |
Dawson, Lesa M. |
title |
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
title_short |
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
title_full |
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
title_fullStr |
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
title_full_unstemmed |
A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
title_sort |
dominant rad51c pathogenic splicing variant predisposes to breast and ovarian cancer in the newfoundland population due to founder effect |
publisher |
John Wiley and Sons Inc. |
publishDate |
2019 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005661/ http://www.ncbi.nlm.nih.gov/pubmed/31782267 https://doi.org/10.1002/mgg3.1070 |
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Newfoundland |
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Newfoundland |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005661/ http://www.ncbi.nlm.nih.gov/pubmed/31782267 http://dx.doi.org/10.1002/mgg3.1070 |
op_rights |
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
op_rightsnorm |
CC-BY |
op_doi |
https://doi.org/10.1002/mgg3.1070 |
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Molecular Genetics & Genomic Medicine |
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8 |
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2 |
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1766106989099745280 |