Population frequency of Predicted pathogenic MisMatch Repair (MMR) gene variants in Lynch syndrome from bioinformatic analyses of the general population.

This study reevaluated the population frequency of Lynch syndrome by analyzing predicted pathogenic variants in mismatch repair (MMR) genes—MLH1, MSH2, MSH6, and PMS2—using data from the gnomAD database.

Prior estimates based on colorectal cancer cohorts suggested about 1 in 300 people carry disease-causing variants. However, by summing structural, null, rare computationally-damaging missense, and founder variants, the authors found a higher frequency:

• 1 in 94 individuals carry predicted pathogenic MMR variants according to their method.

Frequencies varied when using different databases and ClinGen specifications, ranging from 1 in 122 to 1 in 594. These differences reflect variations in variant assessment accuracy and penetrance.

Overall, the findings indicate Lynch syndrome may be more prevalent in the general population than previously reported.