N69: Interpretation Of Inheritable DNA Variation: Room For Error Across Genetic Services?

M. Daly1, J. P. Plazzer2,3, F. Macrae2, 3

1 – Melbourne Medical School, University of Melbourne, Melbourne, Victoria, Australia. 2 – Familial Cancer Centre, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 3 – Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.


Aim: We aimed to evaluate the frequency of conflicts in interpretation of pathogenicity for gene variants in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2 between InSiGHT’s Variant Interpretation Committee (VIC) and those provided by submissions from primary sources to ClinVar.

Method: Variant interpretation submissions for the four genes within ClinVar were compared and with those of the InSiGHT VIC.  Factors that could account for the discordance were assessed including classification guidelines, evidence sources, research only interpretations.

Results: A total of 9,921 unique variant submissions were assessed. 584 interpretation conflicts were identified when compared to the VIC’s classifications. 98 of the conflicts were considered clinically significant. 5,862 variant interpretations have only one submitter. Methods of interpretation by submitters were heterogeneous and included clinical testing, research, and literature searching, accounting for much of the discordance.

Conclusion: Discordant interpretations between submitters represent opportunity for inconsistent counselling for families with the same variant, with potentially serious clinical consequences.  Improvements in data sharing, increased support, coupled with increased awareness of the limitations of current generic methods for variant interpretation, and greater utilisation of expert panels who have access to comprehensive information and use clear gene specific criteria, are essential for optimal interpretation and safe clinical counselling.