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\begin{document}

\title{Rare single-nucleotide variants of MLH1 and MSH2 genes in patients with
Lynch syndrome}



\author[1]{Seyed Mohsen Mirabdolhosseini}%
\author[1]{Mohammad Yaghoob Taleghani}%
\author[1]{Leili Rejali}%
\author[2]{hossein sadeghi}%
\author[1]{Nayeralsadat  Fatemi}%
\author[3]{Mehdi  Tavallaei }%
\author[1]{Amin Famil Meyari}%
\author[1]{Narges Saeidi }%
\author[1]{Amir  Sadeghi }%
\author[1]{Hamid Asadzadeh  Aghdaei}%
\author[1]{Mohammad Reza  Zali}%
\author[1]{Ehsan  Nazemalhosseini Mojarad}%
\affil[1]{Shahid Beheshti University of Medical Sciences Research Institute for Gastroenterology and Liver Diseases}%
\affil[2]{genomic research center, shahid beheshti university Shahid Beheshti University of Medical Sciences}%
\affil[3]{Department of Colorectal Surgery, Medical Science of Shahid Beheshti University, Tehran, Iran}%


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  \date{May 28, 2024}


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\begin{abstract}
Approximately 5\% of colorectal cancers (CRCs) are hereditary. Lynch
syndrome (LS), also known as hereditary nonpolyposis colorectal cancer
(HNPCC), is the most common form of recognized hereditary CRC. Although
Iran, a developing country, has a high incidence of CRC, the spectrum of
mutations has yet to be thoroughly investigated. Therefore, this study
aimed to investigate pathogenic and non-pathogenic variants in MLH1 and
MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). In
the present study, 25 peripheral blood samples were collected from
patients with sLS and high microsatellite instability (MSI-H). After DNA
extraction, all samples underwent polymerase chain reaction (PCR) and
Sanger sequencing to identify the variants in the exons of MLH1 and MSH2
genes. The identified variants were interpreted using prediction tools,
including SIFT, CADD, PolyPhen, PROVEAN, REVEL, MetaLR, and Mutational
Assessor. In our study population, 13 variants were found in the MLH1
gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants
and 3 of the 8 MSH2 variants were novel, whereas the remaining variants
were previously reported or available in databases. In addition, some
patients with sLS did not have variants in the exons of the MLH1 and
MSH2 genes. The variants detected in the MLH1 and MSH2 genes had
specific characteristics regarding the number, area of occurrence, and
their relationship with demographic and clinicopathologic features. We
identified two novel pathogenic/likely pathogenic variants in these two
genes. Overall, our results suggest that analysis of MLH1 and MSH2 genes
alone is insufficient in the Iranian population, and more comprehensive
tests are recommended for detecting LS.%
\end{abstract}%



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