Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon variant c.1A>G of MSH2
- 10 September 2008
- journal article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 17 (2), 159-164
- https://doi.org/10.1038/ejhg.2008.153
Abstract
Mono-allelic germline mutations in mismatch repair (MMR) genes lead to Lynch syndrome, an autosomal dominant syndrome with an increased risk of predominantly colorectal and endometrial cancers. Bi-allelic germline mutations in MMR genes predispose to haematological malignancies, brain tumours, gastrointestinal tumours, polyposis and features of neurofibromatosis type 1 in early childhood. We report a brother and a sister with bi-allelic germline mutations in MSH2; a pathogenic deletion of the first 6 exons and a variant of the initiation codon (c.1A>G (p.Met1?)), whereas their phenotypes (four colorectal cancers, small bowel carcinoma and 15 adenomas at age 39 and 48, and colorectal cancer, endometrial cancer and four adenomas at age 33 and 44, respectively) are more suggestive of a mono-allelic pathogenic MMR gene mutation. The carcinomas showed microsatellite instability in the presence of MLH1, PMS2, MSH2 and MSH6 proteins, indicating that the variant c.1A>G leads to an alternative protein with reduced activity that is retained in the tumours. Our data suggest that the MSH2 variant c.1A>G (p.Met1?) should not be considered as a regular pathogenic mutation that leads to a strongly increased cancer risk, though it possibly contributes to a more severe phenotype when combined with a truncating mutation on the other allele.Keywords
This publication has 25 references indexed in Scilit:
- Constitutive deficiency in DNA mismatch repair: is it time for Lynch III?Clinical Genetics, 2007
- Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 GeneAmerican Journal of Human Genetics, 2003
- Hereditary Colorectal CancerNew England Journal of Medicine, 2003
- Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell typeHuman Genetics, 2003
- Early-Onset Brain Tumor and Lymphoma in MSH2-Deficient ChildrenAmerican Journal of Human Genetics, 2003
- Very low incidence of microsatellite instability in rectal cancers from families at risk for HNPCCClinical Genetics, 2002
- A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots.2002
- Café-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?Familial Cancer, 2001
- The crystal structure of DNA mismatch repair protein MutS binding to a G·T mismatchNature, 2000
- Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 geneOncogene, 2000