ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.943C>T (p.Arg315Ter) (rs200640585)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076901 SCV000108398 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000212858 SCV000149620 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.943C>T at the cDNA level and p.Arg315Ter (R315X) at the protein level. The substitution creates a nonsense variant, changing an Arginine to a premature stop codon (CGA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with colorectal cancer with immunohistochemical tumor testing showing absent PMS2 expression (Vaughn 2010, Borras 2013, Shia 2013, Goodenberger 2016, Sugano 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115711 SCV000212770 pathogenic Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524484 SCV000261298 pathogenic Hereditary nonpolyposis colon cancer 2018-12-02 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg315*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200640585, ExAC 0.01%). This variant has been reported in individuals affected with Lynch syndrome and colon cancer (PMID: 20205264, 23709753, 22918162, 25856668, 27589204). ClinVar contains an entry for this variant (Variation ID: 91382) Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000576503 SCV000677745 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000115711 SCV000691128 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212858 SCV000888422 pathogenic not provided 2017-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763587 SCV000894426 pathogenic Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076901 SCV001338126 pathogenic Lynch syndrome 2020-01-31 criteria provided, single submitter clinical testing Variant summary: PMS2 c.943C>T (p.Arg315X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes. c.943C>T has been reported in the literature in individuals affected with Lynch Syndrome or breast cancer (Susswein_2016, Latham_2019). These data indicate that the variant is likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CSER _CC_NCGL, University of Washington RCV000148734 SCV000190469 pathogenic Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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