Lynch syndrome (LS) is an autosomal dominant inherited disorder, characterized by a predisposition to various cancers, mainly colorectal cancer (CRC). LS is caused by germline mutations in DNA mismatch repair genes i.e. mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post-meiotic segregation increased 2 (PMS2). In this study, we report a novel germline frameshift mutation in the MLH1 gene [NM_000249: exon1: c.99dup p.(Glu34ArgfsTer4)] in a 34-year-old male patient with LS. This MLH1 alteration has never been reported in any database or any publications. The frameshift mutation in MLH1 gene [NM_000249: exon1: c.99dup p.(Glu34ArgfsTer4)] was confirmed by Sanger sequencing conducted on peripheral blood of the proband. Meanwhile, Sanger sequencing results revealed the proband's uncle was the carrier. As multiple downstream germline frameshift mutations of this variation are pathogenic, such as MLH1 M35fs, N38fs, and S44fs, it is predicted that MLH1 p.(Glu34ArgfsTer4) might be also pathogenic. Meanwhile, this MLH1 mutation p.(Glu34ArgfsTer4) is predicted to be disease-causing by the MutationTaster software, as the duplication c.99dupA introduced a premature stop codon early in the translation, resulting in a non-functional protein. This study may contribute to the mutational spectrum of MLH1 leading to LS.
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- Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium.J Clin Oncol. 2006; 24: 4285-4292
- Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications.Clin Genet. 2009; 76: 1-18
- N Engl J Med. 2003; 348: 919-932
- Update on Lynch syndrome genomics.Fam Cancer. 2016; 15: 385-393
- Germline deletions in the EPCAM gene as a cause of Lynch syndrome - literature review.Hered Cancer Clin Pract. 2013; 11: 9
- The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome.Int J Cancer. 2008; 123: 444-449
- Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.World J Gastroenterol. 2007; 13: 2727-2732
- New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.Gastroenterology. 1999; 116: 1453-1456
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Genet Med. 2015; 17: 405-424
Published online: March 18, 2023
Accepted: March 16, 2023
Received in revised form: January 8, 2023
Received: April 22, 2022
© 2023 Published by Elsevier Inc.