ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.765C>A (p.Tyr255Ter) (rs573125799)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162412 SCV000212750 pathogenic Hereditary cancer-predisposing syndrome 2018-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000162412 SCV000911689 pathogenic Hereditary cancer-predisposing syndrome 2018-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000413496 SCV000490729 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.765C>A at the cDNA level and p.Tyr255Ter (Y255X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple individuals with a personal and/or family history of colorectal cancer (Dudley 2015, Goodenberger 2016, Rosty 2016, Yurgelun 2017). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000168447 SCV000920038 pathogenic Lynch syndrome 2017-09-27 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.765C>A (p.Tyr255X) 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. One in silico tool predicts a damaging outcome for this variant. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.823C>T (p.Gln275X), c.861_864delACAG (p.Arg287fsX19), c.1021delA (p.Arg341fsX15)). The variant has been reported in multiple patients with colorectal cancer and other LS-associated tumors from Lynch syndrome families (e.g. Rosty_2016, Yurgelun_2015, Dudley_2015). This variant was found in 1/30666 control chromosomes at a frequency of 0.0000326, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000627717 SCV000219144 pathogenic Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr255*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with Lynch syndrome and colorectal cancer (PMID: 25871621, 23012243, 25980754,25856668). ClinVar contains an entry for this variant (Variation ID: 183716). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168447 SCV000271441 pathogenic Lynch syndrome 2016-03-03 criteria provided, single submitter clinical testing The p.Tyr255X variant in PMS2 has been reported in 2 individuals with PMS2-assoc iated cancers (Dudley 2015, Yurgelun 2015), and was absent from large population studies. This nonsense variant leads to a premature termination codon at positi on 255, which is predicted to lead to a truncated or absent protein. Heterozygou s loss of function of the PMS2 gene is an established disease mechanism in indiv iduals with Lynch syndrome. In summary, this variant meets our criteria to be cl assified as pathogenic for Lynch syndrome in an autosomal dominant manner based upon the predicted impact to the protein.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000413496 SCV000601860 pathogenic not provided 2016-08-04 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000162412 SCV000788119 pathogenic Hereditary cancer-predisposing syndrome 2017-09-07 no assertion criteria provided clinical testing

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