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A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue

The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, a...

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Autores principales: Klančar, Gašper, Blatnik, Ana, Šetrajčič Dragoš, Vita, Vogrič, Vesna, Stegel, Vida, Blatnik, Olga, Drev, Primož, Gazič, Barbara, Krajc, Mateja, Novaković, Srdjan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140785/
https://www.ncbi.nlm.nih.gov/pubmed/32197529
http://dx.doi.org/10.3390/genes11030325
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author Klančar, Gašper
Blatnik, Ana
Šetrajčič Dragoš, Vita
Vogrič, Vesna
Stegel, Vida
Blatnik, Olga
Drev, Primož
Gazič, Barbara
Krajc, Mateja
Novaković, Srdjan
author_facet Klančar, Gašper
Blatnik, Ana
Šetrajčič Dragoš, Vita
Vogrič, Vesna
Stegel, Vida
Blatnik, Olga
Drev, Primož
Gazič, Barbara
Krajc, Mateja
Novaković, Srdjan
author_sort Klančar, Gašper
collection PubMed
description The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel MLH1 in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in MLH1. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel MLH1 variant as likely pathogenic, we confirmed the LS in this family.
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spelling pubmed-71407852020-04-13 A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue Klančar, Gašper Blatnik, Ana Šetrajčič Dragoš, Vita Vogrič, Vesna Stegel, Vida Blatnik, Olga Drev, Primož Gazič, Barbara Krajc, Mateja Novaković, Srdjan Genes (Basel) Article The diagnostics of Lynch syndrome (LS) is focused on the detection of DNA mismatch repair (MMR) system deficiency. MMR deficiency can be detected on tumor tissue by microsatellite instability (MSI) using molecular genetic test or by loss of expression of one of the four proteins (MLH1, MSH2, MSH6, and PMS2) involved in the MMR system using immunohistochemistry (IHC) staining. According to the National Comprehensive Cancer Network (NCCN) guidelines, definitive diagnosis of LS requires the identification of the germline pathogenic variant in one of the MMR genes. In the report, we are presenting interesting novel MLH1 in-frame deletion LRG_216t1:c.2236_2247delCTGCCTGATCTA p.(Leu746_Leu749del) associated with LS. The variant appears to be associated with uncommon isolated loss of PMS2 immunohistochemistry protein staining (expression) in tumor tissue instead of MLH1 and PMS2 protein loss, which is commonly seen with pathogenic variants in MLH1. The variant was classified as likely pathogenic, based on segregation analysis and molecular characterization of blood and tumor samples. According to the American College of Medical Genetics (ACMG) guidelines, the following evidence categories of PM1, PM2, PM4, and PP1 moderate have been used for classification of the novel variant. By detecting and classifying the novel MLH1 variant as likely pathogenic, we confirmed the LS in this family. MDPI 2020-03-18 /pmc/articles/PMC7140785/ /pubmed/32197529 http://dx.doi.org/10.3390/genes11030325 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klančar, Gašper
Blatnik, Ana
Šetrajčič Dragoš, Vita
Vogrič, Vesna
Stegel, Vida
Blatnik, Olga
Drev, Primož
Gazič, Barbara
Krajc, Mateja
Novaković, Srdjan
A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title_full A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title_fullStr A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title_full_unstemmed A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title_short A Novel Germline MLH1 In-Frame Deletion in a Slovenian Lynch Syndrome Family Associated with Uncommon Isolated PMS2 Loss in Tumor Tissue
title_sort novel germline mlh1 in-frame deletion in a slovenian lynch syndrome family associated with uncommon isolated pms2 loss in tumor tissue
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140785/
https://www.ncbi.nlm.nih.gov/pubmed/32197529
http://dx.doi.org/10.3390/genes11030325
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