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

Authors


  • Communicated by Mauno Vihinen

  • Contract Grant sponsors: National Health and Medical Research Council (496616); Cancer Australia (1010859); NIH National Cancer Institute (RFA CA-95-011); Australasian Colorectal Cancer Family Registry (UO1 CA097735); USC Familial Colorectal Neoplasia Collaborative Group (UO1 CA074799); Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (UO1 CA074800); Ontario Registry for Studies of Familial Colorectal Cancer (UO1 CA074783); Seattle Colorectal Cancer Family Registry (UO1 CA074794); University of Hawaii Colorectal Cancer Family Registry (UO1 CA074806); University of California, Irvine Informatics Center (U01 CA078296).

Correspondence to: Bryony A. Thompson, Department of Genetics and Population Health, Queensland Institute of Medical Research, Locked Bag 2000, Royal Brisbane Hospital, Herston, QLD 4029, Australia. E-mail: Bryony.Thompson@qimr.edu.au

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.

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