| Autor: |
Pineda, M., González‐Acosta, M., Thompson, B.A., Sánchez, R., Gómez, C., Martínez‐López, J., Perea, J., Caldés, T., Rodríguez, Y., Landolfi, S., Balmaña, J., Lázaro, C., Robles, L., Capellá, G., Rueda, D. |
| Předmět: |
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| Zdroj: |
Clinical Genetics; Jun2015, Vol. 87 Issue 6, p543-548, 6p, 1 Diagram, 1 Chart, 1 Graph |
| Abstrakt: |
Lynch syndrome ( LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair ( MMR) genes. Variants of unknown significance ( VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c. 121G > C (p. D41H) and c. 2128A > G (p. N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c. 121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c. 2128A > G as a non-pathogenic variant and c. 121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c. 121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c. 121G > C and c. 2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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