LYNCH SYNDROME VARIANT PATHOGENICITY; THE IMPORTANCE OF REVIEWING RISK CLASSIFICATIONS

Aims Lynch syndrome (LS) is the commonest known cause of hereditary colorectal cancer. It is caused by pathogenic variants in the mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2, EPCAM. Variant classification can have a significant effect on management/surveillance choices, whether pathogenic, of uncertain significance or benign. The risk classification of these variants is not permanent and can be upgraded or downgraded over time as more information on that variant becomes available.

The aim of this study is to compare original lab classifications of the hospital cohort of LS patients with up to date classification databases.

Methods A retrospective anonymised gene variant analysis of LS patients from the family clinic database was performed. Specific variants in the MMR genes were identified and their risk classification determined using the CanVar UK and InSiGHT databases.

Results There were 100 LS patients/variants identified. Gene distribution: MSH2 = 48%, MLH1 = 31%, MSH6 = 13%, PMS2 = 8%. The testing took place in 10 different labs. Original test lab classed these variants as Pathogenic = 80 patients, VUS = 1.When the same variants are analysed using the CanVarUK database there are 25 VUS, 3 likely pathogenic. The InSiGHT database gave 7 likely pathogenic and 13 VUS results. Theses variants were subsequently discussed at a genetics MDM and are awaiting review by the original test lab.

Conclusions This study highlights the ever-evolving nature of risk classification in variant analysis. The downgrading of variants from pathogenic to VUS adds a degree of ambiguity to the patient’s diagnosis. It also shows the possible discrepancies that exist between different labs.