A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect
Abstract 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 proban...
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ftdoajarticles:oai:doaj.org/article:85df780709ba4208b36038099c41da29 2024-09-15T18:20:01+00:00 A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect Lesa M. Dawson Kerri N. Smith Salem Werdyani Robyn Ndikumana Cindy Penney Louisa L. Wiede Kendra L. Smith Justin A. Pater Andrée MacMillan Jane Green Sheila Drover Terry‐Lynn Young Darren D. O’Rielly 2020-02-01T00:00:00Z https://doi.org/10.1002/mgg3.1070 https://doaj.org/article/85df780709ba4208b36038099c41da29 EN eng Wiley https://doi.org/10.1002/mgg3.1070 https://doaj.org/toc/2324-9269 2324-9269 doi:10.1002/mgg3.1070 https://doaj.org/article/85df780709ba4208b36038099c41da29 Molecular Genetics & Genomic Medicine, Vol 8, Iss 2, Pp n/a-n/a (2020) founder variant hereditary breast and ovarian cancer RAD51C splicing variant of uncertain significance Genetics QH426-470 article 2020 ftdoajarticles https://doi.org/10.1002/mgg3.1070 2024-08-05T17:49:59Z Abstract 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. Article in Journal/Newspaper Newfoundland Directory of Open Access Journals: DOAJ Articles Molecular Genetics & Genomic Medicine 8 2 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
founder variant hereditary breast and ovarian cancer RAD51C splicing variant of uncertain significance Genetics QH426-470 |
spellingShingle |
founder variant hereditary breast and ovarian cancer RAD51C splicing variant of uncertain significance Genetics QH426-470 Lesa M. Dawson Kerri N. Smith Salem Werdyani Robyn Ndikumana Cindy Penney Louisa L. Wiede Kendra L. Smith Justin A. Pater Andrée MacMillan Jane Green Sheila Drover Terry‐Lynn Young Darren D. O’Rielly A dominant RAD51C pathogenic splicing variant predisposes to breast and ovarian cancer in the Newfoundland population due to founder effect |
topic_facet |
founder variant hereditary breast and ovarian cancer RAD51C splicing variant of uncertain significance Genetics QH426-470 |
description |
Abstract 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. |
format |
Article in Journal/Newspaper |
author |
Lesa M. Dawson Kerri N. Smith Salem Werdyani Robyn Ndikumana Cindy Penney Louisa L. Wiede Kendra L. Smith Justin A. Pater Andrée MacMillan Jane Green Sheila Drover Terry‐Lynn Young Darren D. O’Rielly |
author_facet |
Lesa M. Dawson Kerri N. Smith Salem Werdyani Robyn Ndikumana Cindy Penney Louisa L. Wiede Kendra L. Smith Justin A. Pater Andrée MacMillan Jane Green Sheila Drover Terry‐Lynn Young Darren D. O’Rielly |
author_sort |
Lesa M. Dawson |
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 |
Wiley |
publishDate |
2020 |
url |
https://doi.org/10.1002/mgg3.1070 https://doaj.org/article/85df780709ba4208b36038099c41da29 |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_source |
Molecular Genetics & Genomic Medicine, Vol 8, Iss 2, Pp n/a-n/a (2020) |
op_relation |
https://doi.org/10.1002/mgg3.1070 https://doaj.org/toc/2324-9269 2324-9269 doi:10.1002/mgg3.1070 https://doaj.org/article/85df780709ba4208b36038099c41da29 |
op_doi |
https://doi.org/10.1002/mgg3.1070 |
container_title |
Molecular Genetics & Genomic Medicine |
container_volume |
8 |
container_issue |
2 |
_version_ |
1810458380055085056 |