Characterization of a germline variant MSH6 c.4001G > C in a Lynch syndrome family Journal Article
| Authors: | Yang, C.; Misyura, M.; Kane, S.; Rai, V.; Latham, A.; Zhang, L. |
| Article Title: | 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/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. © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. |
| Keywords: | middle aged; dna binding protein; genetics; dna-binding proteins; case report; endometrial neoplasms; germline; germ cell; pathology; germ cells; lynch syndrome; endometrium tumor; colorectal neoplasms, hereditary nonpolyposis; muts homolog 2 protein; hereditary nonpolyposis colorectal cancer; neoplastic syndromes, hereditary; msh6; humans; human; female; hereditary tumor syndrome; mutl protein homolog 1; dna mismatch repair protein msh2; splice site variant; c.4001g > c |
| Journal Title: | Molecular Genetics and Genomic Medicine |
| Volume: | 11 |
| Issue: | 2 |
| ISSN: | 2324-9269 |
| Publisher: | John Wiley & Sons Ltd. |
| Date Published: | 2023-02-01 |
| Start Page: | e2104 |
| Language: | English |
| DOI: | 10.1002/mgg3.2104 |
| PUBMED: | 36691871 |
| PROVIDER: | scopus |
| PMCID: | PMC9938752 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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