RT Journal Article
SR Electronic
T1 Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 62
OP 69
DO 10.1136/jmedgenet-2019-106096
VO 57
IS 1
A1 Shuwei Li
A1 Dajun Qian
A1 Bryony A Thompson
A1 Stephanie Gutierrez
A1 Sitao Wu
A1 Tina Pesaran
A1 Holly LaDuca
A1 Hsiao-Mei Lu
A1 Elizabeth C Chao
A1 Mary Helen Black
YR 2020
UL http://jmg.bmj.com/content/57/1/62.abstract
AB Background Pathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes.Methods Among 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance of TCLR in combination with in silico predictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed.Results Compared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted with TCLR alone. Models leveraging in silico scores as prior probabilities accurately classified >76.7% variants. Adding TCLR as quantitative evidence in an MVP model (MVP +TCLR Pred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLR Pred resulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.Conclusion Our study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.