{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:04:23Z","timestamp":1771506263533,"version":"3.50.1"},"reference-count":80,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tunisian Ministry of Public Health","award":["LR16IPT05"],"award-info":[{"award-number":["LR16IPT05"]}]},{"name":"Tunisian Ministry of Public Health","award":["EMORI-Horizon2020TN"],"award-info":[{"award-number":["EMORI-Horizon2020TN"]}]},{"name":"Tunisian Ministry of Higher Education and Scientific Research","award":["LR16IPT05"],"award-info":[{"award-number":["LR16IPT05"]}]},{"name":"Tunisian Ministry of Higher Education and Scientific Research","award":["EMORI-Horizon2020TN"],"award-info":[{"award-number":["EMORI-Horizon2020TN"]}]},{"name":"European Union","award":["LR16IPT05"],"award-info":[{"award-number":["LR16IPT05"]}]},{"name":"European Union","award":["EMORI-Horizon2020TN"],"award-info":[{"award-number":["EMORI-Horizon2020TN"]}]},{"name":"National Agency","award":["LR16IPT05"],"award-info":[{"award-number":["LR16IPT05"]}]},{"name":"National Agency","award":["EMORI-Horizon2020TN"],"award-info":[{"award-number":["EMORI-Horizon2020TN"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case \u201cJI-021\u201d, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G&gt;A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G&gt;T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G&gt;A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G&gt;T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.<\/jats:p>","DOI":"10.3390\/genes13081355","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T20:49:28Z","timestamp":1659041368000},"page":"1355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A Rare MSH2 Variant as a Candidate Marker for Lynch Syndrome II Screening in Tunisia: A Case of Diffuse Gastric Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"given":"Maria","family":"Kabbage","sequence":"first","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-7169","authenticated-orcid":false,"given":"Jihenne","family":"Ben Aissa-Haj","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1159-6482","authenticated-orcid":false,"given":"Houcemeddine","family":"Othman","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg 2000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amira","family":"Jaballah-Gabteni","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarra","family":"Laarayedh","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahar","family":"Elouej","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics, Aix Marseille University, INSERM, 13007 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mouna","family":"Medhioub","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haifa","family":"Kettiti","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amal","family":"Khsiba","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moufida","family":"Mahmoudi","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Houda","family":"BelFekih","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Department of Oncology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afifa","family":"Maaloul","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hassen","family":"Touinsi","sequence":"additional","affiliation":[{"name":"Department of Surgery, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamine","family":"Hamzaoui","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emna","family":"Chelbi","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Department of Pathology, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-5525","authenticated-orcid":false,"given":"Sonia","family":"Abdelhak","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Boubaker","sequence":"additional","affiliation":[{"name":"Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia"},{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Azzouz","sequence":"additional","affiliation":[{"name":"Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia"},{"name":"Gastroenterology Department, Mohamed Tahar Maamouri Hospital, Nabeul 8000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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