ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2506G>T (p.Glu836Ter) (rs786201039)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162416 SCV000212756 pathogenic Hereditary cancer-predisposing syndrome 2014-10-17 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000657711 SCV000779460 likely pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2506G>T at the cDNA level and p.Glu836Ter (E836X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through protein truncation. Even though this variant occurs near the end of the gene and nonsense-mediated decay is not expected to occur, it is significant since the last 26 amino acids are no longer translated. Furthermore, the truncation would disrupt a portion of the endonuclease domain and a conserved Zinc binding motif (Kosinski 2008, Fukui 2011). Although this variant has not, to our knowledge, been reported in the literature, it is considered likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657711 SCV001134597 likely pathogenic not provided 2019-01-25 criteria provided, single submitter clinical testing Not found in the gnomAD exomes dataset, and the data is high quality (0/159092 chr). Found in at least one symptomatic patient. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Invitae RCV001066692 SCV001231708 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-09-13 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PMS2 gene (p.Glu836*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 27 amino acids of the PMS2 protein. The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in an individual with suspected Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 183718). This variant disrupts the C-terminal portion of the MLH1 interaction domain (amino acids 675-850) 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). Other variant(s) that disrupt this region (p.Trp841Glyfs*10) have been determined to be pathogenic (PMID: 26116798, 30764633). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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