ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2445+1G>T (rs876661113)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219334 SCV000279559 pathogenic not provided 2018-11-07 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2445+1G>T or IVS14+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 14 of the PMS2 gene. This variant destroys a canonical splice site and is predicted to cause abnormal gene splicing, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Importantly, this variant has been shown to result in the production of an aberrant transcript using patient RNA and minigene analyses (van der Klift 2015). PMS2 c.2445+1G>T has been identified in individuals with suspected Lynch syndrome, including at least three individuals with early onset colorectal cancer and abnormal microsatellite instability testing and/or PMS2 immunohistochemistry (Niessen 2009, Vaughn 2010, ten Broeke 2015, van der Klift 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000228982 SCV000285122 pathogenic Hereditary nonpolyposis colon cancer 2020-01-08 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the PMS2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. The frequency data for this variant in the population databases (ExAC no frequency) 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 confirmed or suspected Lynch syndrome and colorectal cancer (PMID: 19132747, 20205264, 23012243, 25512458, 26110232). ClinVar contains an entry for this variant (Variation ID: 234604). Experimental minigene assays showed that this variant produced aberrant transcripts in HEK293 and HeLa cell lines. Additionally, analysis of patient RNA showed an aberrant PMS2 transcript with retention of 85 bp of flanking intronic sequence (PMID: 26247049). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507182 SCV000604887 pathogenic not specified 2016-08-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575263 SCV000670739 pathogenic Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Functionally-validated splicing mutation
CeGaT Praxis fuer Humangenetik Tuebingen RCV000219334 SCV001247255 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193818 SCV001362952 pathogenic Hereditary nonpolyposis colon cancer 2019-07-16 criteria provided, single submitter clinical testing Variant summary: PMS2 c.2445+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. One publication, van der Klift_2015, reports the variant to result in aberrant transcripts as assessed through minigene assays in HEK293 and HeLa cell lines and also, following analysis of patient RNA where retention of 85bp of flanking intronic sequence was observed. The variant was absent in 194842 control chromosomes (gnomAD). c.2445+1G>T, has been reported in the literature in individuals affected with colorectal cancer (Niessen_2009, Vaughn_2010, ten Broeke_2015). These data indicate that the variant may be associated with disease. Four ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000219334 SCV000691958 pathogenic not provided no assertion criteria provided clinical testing

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