Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000528011 | SCV000625606 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-07-03 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 13 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. 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. Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 31992580, 33193653; Invitae). ClinVar contains an entry for this variant (Variation ID: 455697). Studies have shown that disruption of this splice site results in skipping of exon 13 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV003449547 | SCV004187624 | likely pathogenic | Lynch syndrome 4 | 2023-09-22 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV005000125 | SCV005625944 | likely pathogenic | not provided | 2024-09-20 | criteria provided, single submitter | clinical testing | The PMS2 c.2275+1G>T variant disrupts a canonical splice-donor site and is predicted to interfere with normal PMS2 mRNA splicing. To the best of our knowledge, this variant has not been reported in the published literature. Other variants disrupting this splice site, c.2275+1G>A and c.2275+1G>C, have been reported in individuals with colorectal cancer/Lynch syndrome (PMIDs: 31992580 (2020), 33193653 (2020)). The PMS2 c.2275+1G>T variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. |