Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome

Filomena Cariola, Vittoria Disciglio, Anna M Valentini, Claudio Lotesoriere, Candida Fasano, Giovanna Forte, Luciana Russo, Antonio Di Carlo, Floranna Guglielmi, Andrea Manghisi, Ivan Lolli, Maria L Caruso, Cristiano Simone

Research output: Contribution to journalArticle

Abstract

INTRODUCTION: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols.

CASE DESCRIPTION: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members.

CONCLUSIONS: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

Original languageEnglish
Pages (from-to)1724600818766496
Number of pages6
JournalInternational Journal of Biological Markers
DOIs
Publication statusE-pub ahead of print - Apr 24 2018

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Hereditary Nonpolyposis Colorectal Neoplasms
Genes
DNA Mismatch Repair
Tumors
Repair
Tissue
Microsatellite Instability
Microsatellite Repeats
Proteins
Neoplasms
Bioinformatics
Ports and harbors
Risk assessment
Introns
Germ-Line Mutation
Consensus Sequence
Screening
Computational Biology
Computer Simulation
Cells

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Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome. / Cariola, Filomena; Disciglio, Vittoria; Valentini, Anna M; Lotesoriere, Claudio; Fasano, Candida; Forte, Giovanna; Russo, Luciana; Di Carlo, Antonio; Guglielmi, Floranna; Manghisi, Andrea; Lolli, Ivan; Caruso, Maria L; Simone, Cristiano.

In: International Journal of Biological Markers, 24.04.2018, p. 1724600818766496.

Research output: Contribution to journalArticle

Cariola, Filomena ; Disciglio, Vittoria ; Valentini, Anna M ; Lotesoriere, Claudio ; Fasano, Candida ; Forte, Giovanna ; Russo, Luciana ; Di Carlo, Antonio ; Guglielmi, Floranna ; Manghisi, Andrea ; Lolli, Ivan ; Caruso, Maria L ; Simone, Cristiano. / Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome. In: International Journal of Biological Markers. 2018 ; pp. 1724600818766496.
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T1 - Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome

AU - Cariola, Filomena

AU - Disciglio, Vittoria

AU - Valentini, Anna M

AU - Lotesoriere, Claudio

AU - Fasano, Candida

AU - Forte, Giovanna

AU - Russo, Luciana

AU - Di Carlo, Antonio

AU - Guglielmi, Floranna

AU - Manghisi, Andrea

AU - Lolli, Ivan

AU - Caruso, Maria L

AU - Simone, Cristiano

PY - 2018/4/24

Y1 - 2018/4/24

N2 - INTRODUCTION: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols.CASE DESCRIPTION: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members.CONCLUSIONS: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

AB - INTRODUCTION: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols.CASE DESCRIPTION: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members.CONCLUSIONS: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

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