Anne-Laure Chong, Alejandro Mejia-Garcia, Supriya Behl, Zaki El Haffaf, Sébastien Chénier, Bruno Maranda, Valérie Désilets, Sébastien Lévesque, Lysanne Castonguay, Anne-Marie Mes-Masson, Sylvie Giroux, François Rousseau, Nancy Hamel, George Chong, Simon Gravel, William D Foulkes
{"title":"PMS2 c.2117del (p.Lys706Serfs*19)是加拿大魁北克法裔加拿大人群中最常见的癌症相关始发致病变异。","authors":"Anne-Laure Chong, Alejandro Mejia-Garcia, Supriya Behl, Zaki El Haffaf, Sébastien Chénier, Bruno Maranda, Valérie Désilets, Sébastien Lévesque, Lysanne Castonguay, Anne-Marie Mes-Masson, Sylvie Giroux, François Rousseau, Nancy Hamel, George Chong, Simon Gravel, William D Foulkes","doi":"10.1111/cge.14784","DOIUrl":null,"url":null,"abstract":"<p><p>We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aimed to (a) confirm its founder origin, (b) assess its allele frequency in the FC population, and (c) determine its contribution to the risk of developing various cancers in this population. We identified a haplotype common to all c.2117del alleles spanning 666 kb to 1.37 Mb, confirming the founder nature of the variant. In affected cases, the variant was found in 0 out of 821 breast cancer cases, 8 out of 693 (1.15%) endometrial cancer (EC) cases, and 1 out of 191 (0.52%) colorectal cancer (CRC) cases. In unaffected persons, the variant was identified in 22/6347 newborns (0.35%) and in 21/18129 FC CARTaGENE cohort participants (0.12%). Within this cohort, an excess of CRC (odds ratio: 10.7; 95% CI: 1.42-80.1; p value = 0.022), but not EC, was seen among heterozygotes for the PMS2 founder variant. Analysis of the variant in 24 subregions of Quebec showed over-representation in 5 of them. Here, we report the most frequent genetic cause of mismatch repair deficiency syndromes identified thus far in the FC population of Quebec.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PMS2 c.2117del (p.Lys706Serfs*19) is the Most Frequent Cancer-Associated Founder Pathogenic Variant in the French-Canadian Population of Quebec, Canada.\",\"authors\":\"Anne-Laure Chong, Alejandro Mejia-Garcia, Supriya Behl, Zaki El Haffaf, Sébastien Chénier, Bruno Maranda, Valérie Désilets, Sébastien Lévesque, Lysanne Castonguay, Anne-Marie Mes-Masson, Sylvie Giroux, François Rousseau, Nancy Hamel, George Chong, Simon Gravel, William D Foulkes\",\"doi\":\"10.1111/cge.14784\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aimed to (a) confirm its founder origin, (b) assess its allele frequency in the FC population, and (c) determine its contribution to the risk of developing various cancers in this population. We identified a haplotype common to all c.2117del alleles spanning 666 kb to 1.37 Mb, confirming the founder nature of the variant. In affected cases, the variant was found in 0 out of 821 breast cancer cases, 8 out of 693 (1.15%) endometrial cancer (EC) cases, and 1 out of 191 (0.52%) colorectal cancer (CRC) cases. In unaffected persons, the variant was identified in 22/6347 newborns (0.35%) and in 21/18129 FC CARTaGENE cohort participants (0.12%). Within this cohort, an excess of CRC (odds ratio: 10.7; 95% CI: 1.42-80.1; p value = 0.022), but not EC, was seen among heterozygotes for the PMS2 founder variant. Analysis of the variant in 24 subregions of Quebec showed over-representation in 5 of them. Here, we report the most frequent genetic cause of mismatch repair deficiency syndromes identified thus far in the FC population of Quebec.</p>\",\"PeriodicalId\":10354,\"journal\":{\"name\":\"Clinical Genetics\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical Genetics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1111/cge.14784\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.14784","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
PMS2 c.2117del (p.Lys706Serfs*19) is the Most Frequent Cancer-Associated Founder Pathogenic Variant in the French-Canadian Population of Quebec, Canada.
We identified a PMS2 variant (NM_000535.7:c.2117del, p.Lys706Serfs*19) in 22 French-Canadian (FC) families from Quebec with Lynch syndrome (LS; n = 21) or constitutional mismatch repair deficiency (CMMRD; n = 1). We aimed to (a) confirm its founder origin, (b) assess its allele frequency in the FC population, and (c) determine its contribution to the risk of developing various cancers in this population. We identified a haplotype common to all c.2117del alleles spanning 666 kb to 1.37 Mb, confirming the founder nature of the variant. In affected cases, the variant was found in 0 out of 821 breast cancer cases, 8 out of 693 (1.15%) endometrial cancer (EC) cases, and 1 out of 191 (0.52%) colorectal cancer (CRC) cases. In unaffected persons, the variant was identified in 22/6347 newborns (0.35%) and in 21/18129 FC CARTaGENE cohort participants (0.12%). Within this cohort, an excess of CRC (odds ratio: 10.7; 95% CI: 1.42-80.1; p value = 0.022), but not EC, was seen among heterozygotes for the PMS2 founder variant. Analysis of the variant in 24 subregions of Quebec showed over-representation in 5 of them. Here, we report the most frequent genetic cause of mismatch repair deficiency syndromes identified thus far in the FC population of Quebec.
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease