Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population

Abstract

An increasing number of mismatch-repair (MMR) gene mutations have been identified in hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. This study presents the population-based Danish MMR gene mutation profile, which contains 138 different MMR gene alterations. Among these, 88 mutations in 164 families are considered pathogenic and an additional 50 variants from 76 families are considered to represent variants of unknown pathogenicity. The different MMR genes contribute to 40% (MSH2), 29% (MLH1), and 22% (MSH6) of the mutations and the Danish population thus shows a considerably higher frequency of MSH6 mutations than previously described. Although 69/88 (78%) pathogenic mutations were present in a single family, previously recognized recurrent/founder mutations were causative in 75/137 (55%) MLH1/MSH2 mutant families. In addition, the Danish MLH1 founder mutation c.1667+2_1667_+8TAAATCAdelinsATTT was identified in 14/58 (24%) MLH1 mutant families. The Danish Lynch syndrome population thus demonstrates that MSH6 mutations and recurrent/founder mutations have a larger contribution than previously recognized, which implies that the MSH6 gene should be included in routine diagnostics and suggests that directed analysis of recurrent/founder mutations may be feasible e.g. in families were diagnostic material is restricted to archival tissue.

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

“…the c.1-?_1076+?del, c.942+3A>T and c.1786_1788del have also been reported from Denmark and in Norway (8). Also several of the MSH6 mutations identified, such as c.1444C>T, c.1483C>T, c.2302_2304del, c.3647-2A>C, c.3991C>T and c.4001+2T>C have also been observed in several families from Norway and/or Denmark and these mutations may be of Scandinavian origin.…”

“…The Finnish founder mutation MLH1 c.1732-?_1896+?del, which leads to deletion of MLH1 exon 16, was identified in 6% of our Lynch syndrome families and constituted 15% of the MLH1 families, which is in line with the Finnish ancestry in 5% of the Swedish population. Two families in Sweden carried the Danish founder mutation MLH1 c.1667+2_1667+8delinsATTT (8). Two of the most frequent mutations in the Swedish population, i.e., the MLH1 c.546-2A>G and MSH2 c.1-?_1076+?del (deletion of exons 1-6), have been described as founder mutations in the US (30,31).…”

“…Worldwide, more than 1,300 disease-predisposing MMR gene sequence variants have been reported (4). The estimated contribution from the different MMR genes to Lynch syndrome is ~50% MLH1, ~40% MSH2 (5), 7-20% MSH6 (5)(6)(7)(8) and <5% PMS2 (9). Mutations in the EPCAM gene, located upstream of MSH2, represent an additional cause that is estimated to contribute to 1-3% of the disease-predisposing mutations (10)(11)(12).…”

“…Mutations in the EPCAM gene, located upstream of MSH2, represent an additional cause that is estimated to contribute to 1-3% of the disease-predisposing mutations (10)(11)(12). Founder effects, i.e., mutations that are overrepresented within a geographically or ethically isolated population, have been described in several populations, such as in the different Scandinavian populations (8,13,14) and in the Ashkenazi Jewish population (15)(16)(17)(18).…”

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

“…The c.2252_2253delAA mutation has previously been reported in the InSiGHT LOVD database (http://www.insight-group.org/variants/database/) in a Korean family [35][36][37], a Danish family [38], and in three other occurrences as unpublished data from the UK, Germany and Australia. No details about families nor tumour tissue analysis are available.…”