Discordance between germline genetic findings and abnormal tumor immunohistochemistry staining of mismatch repair proteins in individuals with suspected Lynch syndrome

Abstract

Background and AimsTumor immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins is often used to guide germline genetic testing and variant classification for patients with suspected Lynch syndrome. This analysis examined the spectrum of germline findings in a cohort of individuals showing abnormal tumor IHC.MethodsWe assessed individuals with reported abnormal IHC findings and referred for testing with a six-gene syndrome-specific panel (n=703). Pathogenic variants (PVs) and variants of uncertain significance (VUS) in MMR genes were designated expected/unexpected relative to IHC results.ResultsThe PV positive rate was 23.2% (163/703; 95% confidence interval [CI], 20.1%-26.5%); 8.0% (13/163; 95% CI, 4.3%-13.3%) of PV carriers had a PV in an unexpected MMR gene. Overall, 121 individuals carried VUS in MMR genes expected to be mutated based on IHC results. Based on independent evidence, in 47.1% (57/121; 95% CI, 38.0%-56.4%) of these individuals the VUSs were later reclassified as benign and in 14.0% (17/121; 95% CI, 8.4%-21.5%) of these individuals the VUSs were reclassified as pathogenic.ConclusionsAmong patients with abnormal IHC findings, IHC-guided single-gene genetic testing may miss 8% of individuals with Lynch syndrome. In addition, in patients with VUS identified in MMR genes predicted to be mutated by IHC, extreme caution must be taken when the IHC results are considered in variant classification.

Genotype–phenotype correlations in carriers of the PMS2 founder variant c.1831dup

“…Remarkably, one‐third of tumor samples from the PMS2 c.1831dup PV carriers as well as 17% of those from the PMS2 control group displayed an uncommon IHC pattern. Atypical MMR protein expression patterns have recently been reported in 15.2% of samples from patients with suspected LS (Pan et al., 2023). Another study evaluating patients with PMS2 PVs identified a discordant IHC profile in 6% of their tumor samples after excluding samples with isolated PMS2 loss (van der Klift et al., 2016).…”