ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.809C>G (p.Ser270Ter) (rs786201047)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162437 SCV000212785 pathogenic Hereditary cancer-predisposing syndrome 2019-02-04 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Color RCV000162437 SCV000691119 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Invitae RCV000629674 SCV000750630 pathogenic Hereditary nonpolyposis colon cancer 2019-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ser270*) 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 an individual affected with colorectal cancer (PMID: 25856668) and in individuals with suspected Lynch syndrome (PMID: 28514183). ClinVar contains an entry for this variant (Variation ID: 183732). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657645 SCV000779391 pathogenic not provided 2018-08-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.809C>G at the cDNA level and p.Ser270Ter (S270X) at the protein level. The substitution creates a nonsense variant, which changes a Serine to a premature stop codon (TCA>TGA), 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 an individual with a history of colon cancer and an unaffected individual (Goodenberger 2015, Roberts 2018) and is considered pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657645 SCV000888417 pathogenic not provided 2017-08-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001192582 SCV001360813 pathogenic Lynch syndrome 2019-09-09 criteria provided, single submitter clinical testing Variant summary: PMS2 c.809C>G (p.Ser270X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251328 control chromosomes (gnomAD). c.809C>G has been reported in the literature in an individual affected with colorectal cancer and in individuals with suspected Lynch syndrome (Espenschied_2017, Goodenberger_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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