ClinVar Genomic variation as it relates to human health

This variant is a gross deletion of the genomic region encompassing exons 5-9 of the EPCAM gene. The 5' boundary is likely confined to intron 4. If MSH2 has been tested and no copy number events are reported for it, then the 3’ boundary of this event lies between the EPCAM and MSH2 genes. If MSH2 has not been tested, the 3’ end of this event is unknown as it extends through the termination codon beyond the assayed region for this gene and may encompass additional genes. While this deletion is not anticipated to result in nonsense mediated decay, it is expected to create a truncated protein product or disrupt mRNA translation. Deletions of exons 5-9 have been reported in several families affected with Lynch syndrome (PMID: 21309036). Deletions involving the 3’ region of the EPCAM gene (minimally, exon 9) are known to cause Lynch syndrome. These deletions lead to transcriptional read-through from the EPCAM promoter into the adjacent MSH2 gene, resulting in hypermethylation of the MSH2 promoter and silencing of MSH2 expression (PMID: 19098912, 19177550, 21309036). For these reasons, this variant has been classified as Pathogenic.