Journal article

Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria

Maribel Gonzalez-Acosta, Jesus del Valle, Matilde Navarro, Bryony A Thompson, Silvia Iglesias, Xavier Sanjuan, Maria Jose Paules, Natalia Padilla, Anna Fernandez, Raquel Cuesta, Alex Teule, Guido Plotz, Juan Cadinanos, Xavier de la Cruz, Francesc Balaguer, Conxi Lazaro, Marta Pineda, Gabriel Capella

Familial Cancer | SPRINGER | Published : 2017


The clinical spectrum of germline mismatch repair (MMR) gene variants continues increasing, encompassing Lynch syndrome, Constitutional MMR Deficiency (CMMRD), and the recently reported MSH3-associated polyposis. Genetic diagnosis of these hereditary cancer syndromes is often hampered by the presence of variants of unknown significance (VUS) and overlapping phenotypes. Two PMS2 VUS, c.2149G>A (p.V717M) and c.2444C>T (p.S815L), were identified in trans in one individual diagnosed with early-onset colorectal cancer (CRC) who belonged to a family fulfilling clinical criteria for hereditary cancer. Clinico-pathological data, multifactorial likelihood calculations and functional analyses were use..

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University of Melbourne Researchers


Awarded by FEDER

Awarded by Government of Catalonia

Awarded by Fundacion Mutua Madrilena

Awarded by Red Tematica de Investigacion Cooperativa en Cancer

Funding Acknowledgements

This work was funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds- a way to build Europe-(SAF2012-33636 and SAF2015-68016); the Scientific Foundation Asociacion Espanola Contra el Cancer; the Government of Catalonia (2014SGR338), Fundacion Mutua Madrilena (AP114252013) and Red Tematica de Investigacion Cooperativa en Cancer (RTICC RD12/0036/0031 and RD12/0036/0008). MG-A was supported by grants AP114252013, RD12/0036/0031 and the Scientific Foundation Asociacion Espanola Contra el Cancer. BAT is an NHMRC Early Career Fellow. We are indebted to the patients and the members of the Hereditary Cancer Genetic Counseling Units. We also thank Benjamin Puliafito for the English revision of the manuscript and valuable remarks.