Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000708251 | SCV000837361 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-11-26 | criteria provided, single submitter | clinical testing | This variant is a gross deletion of the genomic region encompassing exon(s) 14 of the PMS2 gene. While this deletion is not anticipated to lead to nonsense mediated decay, it is expected to disrupt the C-terminus of the protein. The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. A similar copy number variant has been observed in individual(s) with clinical features of Lynch syndrome and/or constitutional mismatch repair deficiency syndrome (PMID: 20186688, 23012243, 23288611, 23837913, 26320870; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant disrupts the MLH1 interaction domain of the PMS2 protein, which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). While functional studies have not been performed to directly test the effect of this variant on PMS2 protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. |