Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000630436 | SCV000751392 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2018-03-26 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exons 5-15 of the PMS2 gene. The 5' boundary is likely confined to intron 4. 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. Similar deletions have not been reported in the literature in individuals with PMS2-related disease. No functional studies have been performed to test the effects of this variant on PMS2 protein function or stability. However, it is expected to result in the loss of the last 745 amino acids (118-862) of the protein, which comprises most of the PMS2 protein. In particular, this deletion removes the MLH1 interaction domain (amino acids 675-850), which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723, 12697830), and therefore mismatch repair activity (PMID: 16338176, 20533529). Several missense substitutions in exons 5-15 (p.Lys301Asn, p.Ile668Val and p.Glu705Lys) have been determined to be pathogenic (PMID: 18602922, 26110232, 25856668, 27435373, 25691505, 24027009, 20176959, 26318770, 27601186). This suggests that this region is critical for PMS2 protein function and this deletion variant may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |