Journal article

Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors

M Pineda, M Gonzalez-Acosta, BA Thompson, R Sanchez, C Gomez, J Martinez-Lopez, J Perea, T Caldes, Y Rodriguez, S Landolfi, J Balmana, C Lazaro, L Robles, G Capella, D Rueda

Clinical Genetics | WILEY | Published : 2015


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 ..

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University of Melbourne Researchers


Awarded by Spanish Ministry of Economy and Competitiveness

Awarded by Government of Catalonia

Awarded by Fundacion Mutua Madrilena

Awarded by RTICC MINECO Network

Funding Acknowledgements

We are indebted to the patients and the members of the Hereditary Cancer Genetic Counseling Units. We acknowledge Anna Fernandez for technical support and Adriana Lopez-Doriga for statistical analysis support. This work was funded by the Spanish Ministry of Economy and Competitiveness (grant SAF2012-33636 and grant AES PI10/0683); the Scientific Foundation Asociacion Espanola Contra el Cancer; the Government of Catalonia (grant 2009SGR290), Fundacion Mutua Madrilena (grant AP114252013) and RTICC MINECO Network RD12/0036/0031, RD12/0036/006 and RD12/0036/0008. M. G. is funded by the Fundacion Mutua Madrilena. B. A. T. is supported by a Cancer Council of Queensland PhD Scholarship.