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

作者：Thompson Bryony A^*; Goldgar David E; Paterson Carol; Clendenning Mark; Walters Rhiannon; Arnold Sven; Parsons Michael T; Walsh Michael D; Gallinger Steven; Haile Robert W; Hopper John L; Jenkins Mark A; LeMarchand Loic; Lindor Noralane M; Newcomb Polly A; Thibodeau Stephen N; Young Joanne P; Buchanan Daniel D; Tavtigian Sean V; Spurdle Amanda B

来源：Human Mutation, 2013, 34(1): 200-209.

DOI：10.1002/humu.22213

• unclassified variants
• mismatch repair
• multifactorial likelihood model
• BRAF
• MSI

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 similar to 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. Hum Mutat 34: 200-209, 2013.

• 出版日期2013-1
• 单位河北医科大学