Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family
Abstract Background Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2104 |
| _version_ | 1797903378341167104 |
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| author | Ciyu Yang Maksym Misyura Sarah Kane Vikas Rai Alicia Latham Liying Zhang |
| author_facet | Ciyu Yang Maksym Misyura Sarah Kane Vikas Rai Alicia Latham Liying Zhang |
| author_sort | Ciyu Yang |
| collection | DOAJ |
| description | Abstract Background Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants. Methods The proband was tested via a clinical testing, Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). RT‐PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach. Results We report a 56‐year‐old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein. Conclusion Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic. |
| first_indexed | 2024-04-10T09:31:57Z |
| format | Article |
| id | doaj.art-5f5b5db9029c43c68562281eb0dd665e |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-10T09:31:57Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-5f5b5db9029c43c68562281eb0dd665e2023-02-18T19:05:42ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-02-01112n/an/a10.1002/mgg3.2104Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome familyCiyu Yang0Maksym Misyura1Sarah Kane2Vikas Rai3Alicia Latham4Liying Zhang5Department of Pathology Memorial Sloan Kettering Cancer Center New York New York USADepartment of Pathology Memorial Sloan Kettering Cancer Center New York New York USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York New York USADepartment of Pathology Memorial Sloan Kettering Cancer Center New York New York USADepartment of Medicine Memorial Sloan Kettering Cancer Center New York New York USADepartment of Pathology Memorial Sloan Kettering Cancer Center New York New York USAAbstract Background Germline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants. Methods The proband was tested via a clinical testing, Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). RT‐PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach. Results We report a 56‐year‐old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein. Conclusion Our results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.https://doi.org/10.1002/mgg3.2104c.4001G > CgermlineLynch syndromeMSH6splice site variant |
| spellingShingle | Ciyu Yang Maksym Misyura Sarah Kane Vikas Rai Alicia Latham Liying Zhang Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family Molecular Genetics & Genomic Medicine c.4001G > C germline Lynch syndrome MSH6 splice site variant |
| title | Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family |
| title_full | Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family |
| title_fullStr | Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family |
| title_full_unstemmed | Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family |
| title_short | Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family |
| title_sort | characterization of a germline variant msh6 c 4001g c in a lynch syndrome family |
| topic | c.4001G > C germline Lynch syndrome MSH6 splice site variant |
| url | https://doi.org/10.1002/mgg3.2104 |
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