ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2500_2501delinsG (p.Met834fs) (rs587781626)

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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 RCV000129728 SCV000184533 pathogenic Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000469291 SCV000551942 pathogenic Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing This sequence change is a complex variant in exon 15 of the PMS2 mRNA (c.2500_2501delinsG), causing a frameshift at codon 834. This creates a premature translational stop signal in the last exon of the PMS2 mRNA (p.Met834Glyfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated 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 individuals with clinical features of Lynch syndrome (PMID: 23012243, 25856668, 28514183). It has also been reported to co-occur with a second pathogenic PMS2 variant (c.2T>A) in an individual presenting with phenotypes consistent with constitutional mismatch repair deficiency syndrome (CMMR-D) (Scientific presentation). ClinVar contains an entry for this variant (Variation ID: 141280). 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 loss of the last 29 amino acids (834-862) 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). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587959 SCV000697350 likely pathogenic Lynch syndrome 2017-01-04 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.2500_2501delinsG (p.Met834Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This truncating variant is located in the last exon of the gene. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 30932 control chromosomes. One clinical diagnostic laboratory/reputable database has classified this variant as pathogenic. Additionally, the variant has been reported in one patient with endometrial/breast cancer, two unaffected carriers who were younger than the age of onset of the disease, as well as in one Ambry patient with a second pathogenic variant likely in trans who had colon cancer on both sides of the family. Taken together, this variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759203 SCV000888410 pathogenic not provided 2018-08-05 criteria provided, single submitter clinical testing

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