MISMATCH REPAIR GENE VARIATION IN A COHORT OF IRISH LYNCH SYNDROME PATIENTS

Aims Lynch syndrome (LS) is the commonest known cause of hereditary colorectal cancer, caused by pathogenic variants in the mismatch repair genes (MMR)- MLH1, MSH2, MSH6, PMS2, EPCAM. To date little research has been published on the specific variants that exist in Ireland. Variant classification can have a significant effect on management choices, whether pathogenic, of uncertain significance or benign. Pathogenic MMR variants vary in their predisposition to causing colorectal and gynaecological cancers.

To examine the genetic variants in the LS cohort of patients from a High-Risk Family Colorectal Cancer Screening Clinic.

Methods A retrospective anonymised gene variant analysis of LS patients from the family clinic database. We identified the specific variants in the MMR genes and analysed their risk classification using the CanVar UK and InSight databases.

Results There were 110 LS patients identified, 57 male, 53 female. Gene distribution: MSH2 = 50%, MLH1 = 36%, MSH6 = 13%, PMS2 = 11%. There were 100 patients with documented variants and 34 distinct variants identified. Of these, 13 variants (38%) were identified only once each. Indications for testing included predictive = 82, diagnostic (post-cancer diagnosis = 12). There were 10 different labs used for testing.

Conclusions This updated data raised concerns with isolated single variants, i.e. only one variant existing in the dataset. This may be due of a lack of cascade testing within the same pedigree. Cascade testing of a pedigree should reveal multiples of the same variant. Further testing of family members may be needed to properly risk stratify the family and arrange appropriate and cost-effective GI and non-GI surveillance.