title: Challenges in assessing pathogenicity based on frequency of variants in mismatch repair genes: an extreme case of a MSH2 variant and a meta-analysis.
abstract: The clinical interpretation of variants in mismatch repair (MMR) genes associated with Lynch syndrome can be confusing when the functional nature of the variant is not clearly defined. We report an extreme case where a polymorphism in the MSH2 gene which had a low minor allele frequency, was misclassified as a mutation based on low evidential methods in the database and previous publications. We expanded this experience to perform a systematic meta-analysis in order to investigate other variants that have potentially been misclassified. Our results suggested that the interpretation of pathogenicity should be more cautious and emphasized the need for solid validation through multiple analyses including functional analysis for variants in MMR genes.
authors.affiliation: Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Republic of Korea.
authors.forename: Hye In
authors.initials: HI
authors.lastname: Woo
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Woo
authors.affiliation: Department of Laboratory Medicine, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Republic of Korea.
authors.forename: Sollip
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seung-Tae
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: kimjw@skku.edu.
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000483:Alleles; D003110:Colonic Neoplasms / Q000235:genetics*; D053843:DNA Mismatch Repair; D030561:Databases, Nucleic Acid; D005260:Female; D005787:Gene Frequency; D006801:Humans; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: Lynch syndrome; MLH1; MMR; MSH6; VUS