How to identify and classify low penetrant variants, in casu PMS2?

Pål Møller

Oslo University Hospital, Norway


Current understanding of path_PMS2 demonstrates a series of cognitive misconceptions:

  • Lynch syndrome is an inherited cancer syndrome
  • Carriers without cancer do not have Lynch syndrome
  • Path_PMS2 variants cause the recessively inherited cancer syndrome CMMRD
  • The UK NICE guidelines define Lynch syndrome as a cancer syndrome with high penetrance: path_PMS2 variants are not causing a high penetrant dominantly inherited cancer syndrome: path_PMS2 variants are not causing Lynch syndrome
  • Prevalence of path_PMS2 variants is unknown because we don’t know how to identify them: The InSiGHT criteria for pathogenicity are tailored to identify high penetrant variants for dominantly inherited disorders, which path_PMS2 variants are not.
  • Clinical criteria for who to subject to genetic testing are selecting high penetrant variants, which is also why the prevalence of path_PMS2 variants reported is erroneously low
  • Cancer incidence in heterozygote path_PMS2 carriers is hardly increased, but some variants seem associated with cancer in older ages (in genetic terminology denoted heterozygote manifestations in recessively inherited disorders)
  • Genetic variants causing recessively inherited disorders with heterozygote manifestations in older ages (not reduced fitness) may be frequent (cfr thalassemia; cystic fibrosis, etc.)

To identify low penetrant genetic variants associated with cancer, we need a new set of criteria tailored in keeping with the above arguments.