A rare large duplication of MLH1 identified in Lynch syndrome
Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated...
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| Format: | Article |
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BMC
2021-01-01
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| Series: | Hereditary Cancer in Clinical Practice |
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| Online Access: | https://doi.org/10.1186/s13053-021-00167-0 |
| _version_ | 1828891469639843840 |
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| author | Abhishek Kumar Nagarajan Paramasivam Obul Reddy Bandapalli Matthias Schlesner Tianhui Chen Rolf Sijmons Dagmara Dymerska Katarzyna Golebiewska Magdalena Kuswik Jan Lubinski Kari Hemminki Asta Försti |
| author_facet | Abhishek Kumar Nagarajan Paramasivam Obul Reddy Bandapalli Matthias Schlesner Tianhui Chen Rolf Sijmons Dagmara Dymerska Katarzyna Golebiewska Magdalena Kuswik Jan Lubinski Kari Hemminki Asta Försti |
| author_sort | Abhishek Kumar |
| collection | DOAJ |
| description | Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons. |
| first_indexed | 2024-12-13T13:17:40Z |
| format | Article |
| id | doaj.art-c6c2f828357c45e385e949c16fb13d9e |
| institution | Directory Open Access Journal |
| issn | 1897-4287 |
| language | English |
| last_indexed | 2024-12-13T13:17:40Z |
| publishDate | 2021-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Hereditary Cancer in Clinical Practice |
| spelling | doaj.art-c6c2f828357c45e385e949c16fb13d9e2022-12-21T23:44:29ZengBMCHereditary Cancer in Clinical Practice1897-42872021-01-011911710.1186/s13053-021-00167-0A rare large duplication of MLH1 identified in Lynch syndromeAbhishek Kumar0Nagarajan Paramasivam1Obul Reddy Bandapalli2Matthias Schlesner3Tianhui Chen4Rolf Sijmons5Dagmara Dymerska6Katarzyna Golebiewska7Magdalena Kuswik8Jan Lubinski9Kari Hemminki10Asta Försti11Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ)Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT)Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ)Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ)Department of Cancer Prevention, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine, Chinese Academy of SciencesDepartment of Genetics, University Medical Center Groningen, University of GroningenHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical UniversityHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical UniversityHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical UniversityHereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical UniversityDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ)Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ)Abstract Background The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation. Methods In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families. Results Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site. Conclusions We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.https://doi.org/10.1186/s13053-021-00167-0Genetic predispositionLynch syndromeMismatch repair genesWhole-genome sequencing |
| spellingShingle | Abhishek Kumar Nagarajan Paramasivam Obul Reddy Bandapalli Matthias Schlesner Tianhui Chen Rolf Sijmons Dagmara Dymerska Katarzyna Golebiewska Magdalena Kuswik Jan Lubinski Kari Hemminki Asta Försti A rare large duplication of MLH1 identified in Lynch syndrome Hereditary Cancer in Clinical Practice Genetic predisposition Lynch syndrome Mismatch repair genes Whole-genome sequencing |
| title | A rare large duplication of MLH1 identified in Lynch syndrome |
| title_full | A rare large duplication of MLH1 identified in Lynch syndrome |
| title_fullStr | A rare large duplication of MLH1 identified in Lynch syndrome |
| title_full_unstemmed | A rare large duplication of MLH1 identified in Lynch syndrome |
| title_short | A rare large duplication of MLH1 identified in Lynch syndrome |
| title_sort | rare large duplication of mlh1 identified in lynch syndrome |
| topic | Genetic predisposition Lynch syndrome Mismatch repair genes Whole-genome sequencing |
| url | https://doi.org/10.1186/s13053-021-00167-0 |
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