ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2174+1G>C

dbSNP: rs267608172
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001387075 SCV001587569 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-12-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 12 of the PMS2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened 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 colorectal cancer, breast cancer, ovarian cancer, pancreatic cancer, suspected Lynch syndrome, and constitutional mismatch repair deficiency syndrome (PMID: 18602922, 20205264, 21376568, 23012243, 25186627, 26110232, 26681312, 28135145, 30067863). ClinVar contains an entry for this variant (Variation ID: 1073933). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 21376568, 26247049). 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.
Myriad Genetics, Inc. RCV003450073 SCV004187646 likely pathogenic Lynch syndrome 4 2023-09-21 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.

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