Abstract
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 used to refine their clinical significance. Likelihood analysis based on cosegregation and tumor data classified the c.2444C>T variant as pathogenic, which was supported by impaired MMR activity associated with diminished protein expression in functional assays. Conversely, the c.2149G>A variant displayed MMR proficiency and protein stability. These results, in addition to the conserved PMS2 expression in normal tissues and the absence of germline microsatellite instability (gMSI) in the biallelic carrier ruled out a CMMRD diagnosis. The use of comprehensive strategies, including functional and clinico-pathological information, is mandatory to improve the clinical interpretation of naturally occurring MMR variants. This is critical for appropriate clinical management of cancer syndromes associated to MMR gene mutations.
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Abbreviations
- CMMRD:
-
Constitutional mismatch repair deficiency
- CRC:
-
Colorectal cancer
- gMSI:
-
Germline microsatellite instability
- LR:
-
Likelihood ratio
- LS:
-
Lynch syndrome
- MMR:
-
Mismatch repair
- MSI:
-
Microsatellite instability
- VUS:
-
Variant of unknown significance
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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 Asociación Española Contra el Cáncer; the Government of Catalonia (2014SGR338), Fundación Mutua Madrileña (AP114252013) and Red Temática de Investigación Cooperativa en Cáncer (RTICC RD12/0036/0031 and RD12/0036/0008). MG-A was supported by grants AP114252013, RD12/0036/0031 and the Scientific Foundation Asociación Española Contra el Cáncer. 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.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Marta Pineda and Gabriel Capellá have contributed equally to this work and share senior authorship.
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González-Acosta, M., del Valle, J., Navarro, M. et al. Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria. Familial Cancer 16, 501–507 (2017). https://doi.org/10.1007/s10689-017-9981-1
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DOI: https://doi.org/10.1007/s10689-017-9981-1