Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.
Lynch syndrome caused by constitutional mismatch‑repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations.
Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
Kristina
K
Lagerstedt-Robinson
Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden.
Anna
A
Rohlin
Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden.
Christos
C
Aravidis
Department of Radiation Sciences, Division of Oncology, Umeå University, SE-90187 Umeå, Sweden.
Beatrice
B
Melin
Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden.
Margareta
M
Nordling
Department of Oncology, Linköping University, SE-58183 Linköping, Sweden.
Marie
M
Stenmark-Askmalm
Department of Molecular Medicine and Surgery, Karolinska Institute and Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden.
Annika
A
Lindblom
Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, SE-22381 Lund, Sweden.
Mef
M
Nilbert
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D017384:Sequence Deletion; D013548:Sweden
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein