ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1882C>T (p.Arg628Ter) (rs63750451)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076834 SCV000108321 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000218575 SCV000277667 pathogenic Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000220439 SCV000279234 pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.1882C>T at the cDNA level and p.Arg628Ter (R628X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>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 several individuals with Lynch syndrome (Hendriks 2006, ten Broeke 2015, Suerink 2015) and is considered pathogenic.
Invitae RCV000524451 SCV000551972 pathogenic Hereditary nonpolyposis colon cancer 2019-12-11 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg628*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63750451, ExAC 0.02%). This particular variant has been reported in the literature in individuals and families affected with Lynch syndrome (PMID: 16472587, 26110232, 25512458, 27435373, 27589204) and in the homozygous state in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 19283792). ClinVar contains an entry for this variant (Variation ID: 9242). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000009823 SCV000745188 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2016-03-16 criteria provided, single submitter clinical testing
Color RCV000218575 SCV000905473 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193819 SCV001362953 pathogenic Lynch syndrome 2019-06-24 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1882C>T (p.Arg628X) 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. RT-PCR analysis on RNA derived from cultured lymphocytes of patients carrying the variant demonstrated nonsense-mediated RNA decay (van der Klift_2010, 2016). The variant allele was found at a frequency of 1.6e-05 in 251434 control chromosomes (gnomAD). c.1882C>T has been reported in the literature in multiple individuals affected with Lynch Syndrome (Hendriks_2006, Sugano_2016, van der Klift_2010, 2016). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000009823 SCV000030044 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2006-02-01 no assertion criteria provided literature only
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000009823 SCV000734561 pathogenic Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing

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