ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2522G>A (p.Trp841Ter) (rs876661203)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217259 SCV000279779 likely pathogenic not provided 2016-01-08 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2522G>A at the cDNA level and p.Trp841Ter (W841X) at the protein level. The substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG) , and is predicted to cause loss of normal protein function through protein truncation. Even though this frameshift occurs near the end of the gene in the last exon, and nonsense-mediated decay is not expected to occur, it is significant since the last 22 amino acids are no longer translated. Furthermore, the truncation would disrupt the nuclease domain (Fukui 2011). In addition, functional studies have shown that downstream residues are involved with zinc binding and variants at these downstream residues result in significant reduction of MMR activity (Kosinski 2008). Therefore, we consider this variant to be likely pathogenic.
Invitae RCV000533097 SCV000625624 likely pathogenic Hereditary nonpolyposis colon cancer 2017-05-03 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the PMS2 mRNA at codon 841 (p.Trp841*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 22 amino acids of the PMS2 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234759). A different variant (c.2523G>A) giving rise to the same protein effect observed here (p.Trp841*) has been reported in an individual affected with breast or ovarian cancer (PMID: 24549055), indicating that this residue may be critical for protein function. 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 disruption of the last 22 amino acids (Trp841-Asn862) of the PMS2 protein. This removes the C-terminal portion of the MLH1 interaction domain (amino acids 675-850), which has been shown to be critical for PMS2-MLH1 dimerization (PMID: 10037723), and therefore mismatch repair activity (PMID: 16338176, 20533529). In summary, this variant removes the C-terminal portion of the MLH1 interacting domain of the PMS2 protein, and although it has not been reported in the literature a different variant causing the same effect has been found in an affected individual. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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