RT info:eu-repo/semantics/article
T1 Evaluating the Effect of Unclassified Variants Identified in MMR Genes Using Phenotypic Features, Bioinformatics Prediction, and RNA Assays
A1 Pérez-Cabornero, Lucia
A1 Infante Sanz, María Del Mar
A1 Velasco, Eladio
A1 Lastra, Enrique
A1 Miner, Cristina
A1 Duran Dominguez, María Mercedes
AB Lynch syndrome is caused by mutations in one of the mismatch-repair system (MMR) genes. A major difficulty in diagnosis and management of Lynch syndrome is the existence of unclassified genetic variants (UVs) with unknown clinical significance, especially mutations with new descriptions and missense-type nucleotide substitutions. We evaluated the pathogenicity of 20 such mutations (6 in MLH1, 4 in MSH2, and 7 in MSH6) found in Spanish patients suspected of Lynch syndrome. The UVs were tested for evidence of MMR defect in tumor samples and were evaluated for co-occurrence with a pathogenic mutation, the cosegregation of the variant with the disease; where sufficient data were available, in silico resources at the protein level and mRNA analysis were used to assess the putative effect on the splicing mechanism. To evaluate the frequency of these UVs in the general population, a case–control study was also performed. Five variants were identified with similar frequencies in both cases and controls, suggesting a nonpathogenic effect in patients. In contrast, abnormal splicing mutations were detected in a high proportion of patients [3/20 (15%)]. In this study, we classified 15 of the 20 UVs: six variants with strong evidence of pathogenicity and nine variants that should be considered neutral variants. Clinical significance of the other five remains unknown.
PB Elsevier
SN 1525-1578
YR 2013
FD 2013-05
LK https://uvadoc.uva.es/handle/10324/64663
UL https://uvadoc.uva.es/handle/10324/64663
LA spa
NO The Journal of Molecular Diagnostics Volume 15, Issue 3, May 2013, Pages 380-390
DS UVaDOC
RD 27-dic-2024