Comprehensive functional assessment of MLH1 variants of unknown significance
Por:
Borras, E, Pineda, M, Brieger, A, Hinrichsen, I, Gomez, C, Navarro, M, Balmana, J, Cajal, TRY, Torres, A, Brunet, J, Blanco, I, Plotz, G, Lazaro, C, Capella, G
Publicada:
1 nov 2012
Resumen:
Lynch syndrome is associated with germline mutations in DNA mismatch repair (MMR) genes. Up to 30% of DNA changes found are variants of unknown significance (VUS). Our aim was to assess the pathogenicity of eight MLH1 VUS identified in patients suspected of Lynch syndrome. All of them are novel or not previously characterized. For their classification, we followed a strategy that integrates family history, tumor pathology, and control frequency data with a variety of in silico and in vitro analyses at RNA and protein level, such as MMR assay, MLH1 and PMS2 expression, and subcellular localization. Five MLH1 VUS were classified as pathogenic: c.[248G>T(;)306G>C], c.[780C>G;788A>C], and c.791-7T>A affected mRNA processing, whereas c.218T>C (p.L73P) and c.244G>A (p.T82A) impaired MMR activity. Two other VUS were considered likely neutral: the silent c.702G>A variant did not affect mRNA processing or stability, and c.974G>A (p.R325Q) did not influence MMR function. In contrast, variant c.25C>T (p.R9W) could not be classified, as it associated with intermediate levels of MMR activity. Comprehensive functional assessment of MLH1 variants was useful in their classification and became relevant in the diagnosis and genetic counseling of carrier families. Hum Mutat 33:15761588, 2012. (c) 2012 Wiley Periodicals, Inc.
Filiaciones:
Borras, E:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Pineda, M:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Brieger, A:
Johann Wolfgang Goethe Univ Clin, Med Clin 1, Frankfurt, Germany
Hinrichsen, I:
Johann Wolfgang Goethe Univ Clin, Med Clin 1, Frankfurt, Germany
Gomez, C:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Navarro, M:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Balmana, J:
Hosp Univ Vall dHebron, Med Oncol Serv, Barcelona, Spain
Cajal, TRY:
Hosp Santa Creu & Sant Pau, Med Oncol Serv, Barcelona, Spain
Torres, A:
Hosp Univ St Joan, Unitat Consell Genet, Reus, Spain
Brunet, J:
ICO IdIBGI, Hereditary Canc Program, Catalan Inst Oncol, Girona, Spain
Blanco, I:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Plotz, G:
Johann Wolfgang Goethe Univ Clin, Med Clin 1, Frankfurt, Germany
Lazaro, C:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
Capella, G:
ICO IDIBELL, Hereditary Canc Program, Catalan Inst Oncol, Lhospitalet De Llobregat, Spain
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