Table 9.

Lynch Syndrome: Gene-Specific Laboratory Considerations

Gene 1Special Consideration
EPCAM Only large deletions that incl the last exon of EPCAM are causative of Lynch syndrome; other EPCAM variants are not assoc w/Lynch syndrome [Arnold et al 2020].
MLH1 Constitutional inactivation of the MLH1 promoter by methylation, along w/somatic loss of heterozygosity of the functional allele, has been reported as a rare cause of Lynch syndrome. Most instances of MLH1 promoter methylation are simplex (i.e., a single occurrence in a family), but a few families w/inherited hypermethylation have been reported [Hitchins 2015]. MLH1 promoter methylation is not detectable by either sequence analysis or duplication/deletion analysis of MLH1.
PMS2 Molecular analysis of PMS2 is more complex due to the presence of multiple PMS2 pseudogenes. The presence of genomic regions w/high sequence homology to PMS2 hampers conventional analysis. Long-range PCR, cDNA sequencing, or specific solutions to NGS testing can help distinguish between PMS2 pathogenic variants & pseudogene variants [Li et al 2015a, Lee et al 2021].
1.

Genes in alphabetic order

From: Lynch Syndrome

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