title: A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.
abstract: Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.
authors.affiliation: Department of Genetics and Population Health, Queensland Institute of Medical Research, Herston, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia.
authors.forename: Bryony A
authors.initials: BA
authors.lastname: Thompson
authors.forename: David E
authors.initials: DE
authors.lastname: Goldgar
authors.forename: Carol
authors.initials: C
authors.lastname: Paterson
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Walters
authors.forename: Sven
authors.initials: S
authors.lastname: Arnold
authors.forename: Michael T
authors.initials: MT
authors.lastname: Parsons
authors.forename: Walsh
authors.initials: W
authors.lastname: Michael D
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Loic
authors.initials: L
authors.lastname: Lemarchand
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics*; D019295:Computational Biology / Q000145:classification / Q000379:methods* / Q000706:statistics & numerical data; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods / Q000706:statistics & numerical data; D004268:DNA-Binding Proteins / Q000235:genetics; D005192:Family Health; D006801:Humans; D016013:Likelihood Functions; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012042:Registries / Q000145:classification / Q000706:statistics & numerical data
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein