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Original article
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity
  1. Shuwei Li1,
  2. Dajun Qian1,
  3. Bryony A Thompson2,3,
  4. Stephanie Gutierrez4,
  5. Sitao Wu1,
  6. Tina Pesaran4,
  7. Holly LaDuca4,
  8. Hsiao-Mei Lu1,
  9. Elizabeth C Chao4,
  10. Mary Helen Black1
  1. 1 Bioinformatics, Ambry Genetics Corp, Aliso Viejo, California, USA
  2. 2 Royal Melbourne Hospital, Melbourne, Victoria, Australia
  3. 3 Department of Clinical Pathology, University of Melbourne, Parkville, Victoria, Australia
  4. 4 Clinical Diagnostics, Ambry Genetics Corp, Aliso Viejo, California, USA
  1. Correspondence to Dr Mary Helen Black, Bioinformatics, Ambry Genetics Corp, Aliso Viejo, CA 92656, USA; mblack{at}


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.

  • clinical genetics
  • cancer: colon
  • mismatch repair genes
  • MSI
  • IHC

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  • Correction notice This article has been corrected since it was published Online First. The name of one of the authors (Mary Helen Black) has been corrected.

  • Contributors MHB and SL contributed to the concept and design. SL, DQ, SG and SW contributed to the acquisition, analysis and interpretation of data. SL drafted the manuscript; MHB, SL, BAT, DQ, TP, ECC, HL, HML contributed to the critical revision of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests All other authors are employed by and receive a salary from Ambry Genetics.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.