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Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome

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dc.contributor.author Castillejo, Adela
dc.contributor.author Guarinos, Carla
dc.contributor.author Martínez Canto, Ana
dc.contributor.author Barbera, Victor Manuel
dc.contributor.author Egoavil, Cecilia
dc.contributor.author Castillejo, Maria Isabel
dc.contributor.author Pérez Carbonell, Lucía
dc.contributor.author Sánchez Heras, Ana Beatriz
dc.contributor.author Segura, Ángel
dc.contributor.author Ochoa, Enrique
dc.contributor.author Lazaro, Rafael
dc.contributor.author Ruiz Ponte, Clara
dc.contributor.author Bujanda, Luis
dc.contributor.author Andreu García, Montserrat
dc.contributor.author Castells, Antoni
dc.contributor.author Carracedo, Ángel
dc.contributor.author Llor, Xavier
dc.contributor.author Clofent, Juan
dc.contributor.author Alenda, Cristina
dc.contributor.author Paya, Artemio
dc.contributor.author Jover, Rodrigo
dc.contributor.author Soto, José Luis
dc.date.accessioned 2012-05-11T07:29:17Z
dc.date.available 2012-05-11T07:29:17Z
dc.date.issued 2011
dc.identifier.citation Castillejo A, Guarinos C, Martinez-Canto A, Barbera VM, Egoavil C, Castillejo MI et al. Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome. BMC Med. Genet. 2011;12:12. DOI: 10.1186/1471-2350-12-12
dc.identifier.issn 1471-2350
dc.identifier.uri http://hdl.handle.net/10230/16455
dc.description.abstract Background: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS./nMethods: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers./nResults: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients./nConclusions: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof BMC Medical Genetics. 2011;12:12
dc.rights © 2011 Castillejo et al. Creative Commons Attribution License
dc.rights.uri http://creativecommons.org/licenses/by/2.0/
dc.subject.other Càncer -- Aspectes genètics
dc.subject.other Malalties congènites
dc.subject.other Genètica de poblacions humanes
dc.title Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1186/1471-2350-12-12
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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