1. ¹Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
2. ²Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Correspondence: CM Kets, Radboud University Nijmegen Medical Centre, 849 Human Genetics, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 243613946; Fax: +31 243668774; E-mail: m.kets@antrg.umcn.nl

Received 4 December 2007; Revised 17 July 2008; Accepted 23 July 2008; Published online 10 September 2008.

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.