ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2192_2196del (p.Leu731fs) (rs63750695)

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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 RCV000163763 SCV000214343 pathogenic Hereditary cancer-predisposing syndrome 2017-02-08 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),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Counsyl RCV000662653 SCV000785340 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-07-07 criteria provided, single submitter clinical testing
GeneDx RCV000486374 SCV000567287 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing This deletion of 5 nucleotides in PMS2 is denoted c.2192_2196delTAACT at the cDNA level and p.Leu731CysfsX3 (L731CfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AACT[delTAACT]GCTG. The deletion causes a frameshift, which changes a Leucine to a Cysteine at codon 731, and creates a premature stop codon at position 3 of the new reading frame. This variant was demonstrated by RT-PCR to cause nonsense-mediated mRNA decay and by Western blot to lead to abrogation of the PMS2 protein (Nakagawa 2004, van der Klift 2010). PMS2 c.2192_2196delTAACT has been observed in association with early onset colorectal cancer, with at least one tumor demonstrating loss of PMS2 protein on immunohistochemistry (IHC) and loss of heterozygosity (Nakagawa 2004, Senter 2008). We consider this variant to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076846 SCV000108336 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Coding sequence variation resulting in a stop codon
Invitae RCV000524460 SCV000285108 pathogenic Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 13 of the PMS2 mRNA (c.2192_2196delTAACT), causing a frameshift at codon 731. This creates a premature translational stop signal (p.Leu731Cysfs*3) and is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with Lynch syndrome (PMID: 15872200, 20186688). ClinVar contains an entry for this variant (Variation ID: 91331). 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 RCV000076846 SCV000271440 pathogenic Lynch syndrome 2016-03-03 criteria provided, single submitter clinical testing The p.Leu731fs variant in PMS2 has been reported in 3 individuals with PMS2-asso ciated cancers (Nakagawa 2004, Hampel 2005, van der Klift 2010). This variant ha s been identified in 1/10208 Latino chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750695). This variant is pr edicted to cause a frameshift, which alters the protein?s amino acid sequence be ginning at position 731 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established diseas e mechanism in individuals with Lynch syndrome. In summary, this variant meets o ur criteria to be classified as pathogenic for Lynch syndrome in an autosomal do minant manner based upon predicted impact to the protein. ACMG/AMP Criteria appl ied: PVS1, PM2, PS4_Supporting.
Mendelics RCV000076846 SCV000838169 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000076846 SCV000266119 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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