title: Elucidating the clinical significance of two PMS2 missense variants coexisting in a family fulfilling hereditary cancer criteria.
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.
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: González-Acosta
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Del Valle
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.|Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: Bryony A
authors.initials: BA
authors.lastname: Thompson
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Iglesias
authors.affiliation: Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sanjuan
authors.affiliation: Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Paúles
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
authors.forename: Natàlia
authors.initials: N
authors.lastname: Padilla
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fernández
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cuesta
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Àlex
authors.initials: À
authors.lastname: Teulé
authors.affiliation: Medical Clinic 1, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Plotz
authors.affiliation: Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), Oviedo, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Cadiñanos
authors.affiliation: Research Unit in Translational Bioinformatics, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.|ICREA, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: de la Cruz
authors.affiliation: Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Balaguer
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Hereditary Cancer Program, Catalan Institute of Oncology (ICO), IDIBELL and CIBERONC, Av. Gran Via de l'Hospitalet, 199-203, 08908, Hospitalet de Llobregat (Barcelona), Spain. gcapella@iconcologia.net.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capellá
mesh_terms: D017668:Age of Onset; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D005260:Female; D005787:Gene Frequency; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000235:genetics; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree
chemical_list: C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2
keywords: Constitutional mismatch repair deficiency; Lynch syndrome; Mismatch repair; PMS2 gene; Variant of unknown significance