Compound heterozygosity for two MSH2 mutations suggests mild consequences of the initiation codon mutation c.1A>G of MSH2

M. Kets, N. Hoogerbrugge, J.H.J.M. van Krieken, M. Goossens, H.G. Brunner, M.J.L. Ligtenberg
Department of Human Genetics, Radboud University Nijmegen Medical Centre

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 tumors, 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 an alteration of the initiation codon (c.1A>G (p.Met1?)), while their phenotypes (4 colorectal cancers, small bowel carcinoma and 15 adenomas at age 39 and 48, and colorectal cancer, endometrial cancer and 4 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 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.