Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Abstract

Abstract. 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.

Hereditary colorectal cancer diagnostics in southern Sweden: retrospective evaluation and future considerations with emphasis on Lynch syndrome

“…Slightly higher values (53–62%) have been obtained in other Scandinavian cohorts (Lagerstedt Robinson et al 2007; Sjursen et al 2010). The distribution of mutations in the MMR genes in our cohort is largely similar to that recently reported in a Swedish national LS cohort, i.e., mutations in MLH1 and MSH2 predominate (Lagerstedt-Robinson et al 2016). …”

Expanding clinical phenotype in CACNA1C related disorders: From neonatal onset severe epileptic encephalopathy to late‐onset epilepsy

“…Additional findings on ES included a heterozygous, de novo, and terminal deletion of MSH2 . This deletion involves exons 11–16 ([NM_000251.2] arr[GRCh37] 2p21(47,695,322–47,710,345) × 1) of the gene and has been previously reported as pathogenic of hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome) in several families (Lagerstedt‐Robinson et al, ; Martínez‐Bouzas et al, ; McPhillips, Meldrum, Creegan, Edkins, & Scott, ; Romero et al, ).…”

Familial Associations of Colorectal Cancer with Other Cancers

“…However, to put the scope of our study in perspective, a recent study reported that 369 Lynch syndrome families were identified in Sweden but no information was given on how many persons were tested for mutations 15 . The authors estimated that no more than one-quarter of the mutation carriers had been identified in Sweden which may imply that some 1500 Lynch syndrome families would exist.…”