Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000240047 | SCV000299159 | pathogenic | Lynch syndrome | 2016-03-30 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 3-15 of the PMS2 gene. The 5' boundary is likely confined to intron 2. 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 by eliminating 808 amino acid residues (~94%) from the full length PMS2 protein. Truncating variants including sub-genic gross deletions in PMS2 are known to be pathogenic. While deletions of exons 3-15 have not been reported in the literature, a similar deletion of exons (3-) 5-15 has been reported in an individual with Lynch syndrome-associated cancer, but it is not clear if the deletion encompasses exons 3-15 or 5-15 (PMID: 20186688, 25512458). This large truncation is expected to remove important PMS2 functional domains, including a coiled-coil domain (residues 612-674) that mediates the interaction with MLH1, which is required for mismatch repair activity (PMID: 11292842). Smaller in-frame deletions of exons 6-8 and 8-11 have been classified as pathogenic (Invitae database). For these reasons, this variant has been classified as Pathogenic. |