A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome
1 Department of Medical Genetics, University Medical Centre Utrecht, Lundlaan 6, Utrecht, The Netherlands
2 Family Cancer Clinic and Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands
3 Department of Pathology, St. Antonius Hospital, Koekoekslaan 1, Nieuwegein, The Netherlands
4 Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, Groningen, The Netherlands
5 Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, The Netherlands
6 Department of Clinical Genetics, VU University Medical Centre, De Boelelaan 1117, Amsterdam, The Netherlands
Hereditary Cancer in Clinical Practice 2010, 8:7 doi:10.1186/1897-4287-8-7Published: 12 August 2010
An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.
We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.
The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.
We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.