ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.400C>T (p.Arg134Ter) (rs63750871)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115695 SCV000187198 pathogenic Hereditary cancer-predisposing syndrome 2018-03-02 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)
Color RCV000115695 SCV000686201 pathogenic Hereditary cancer-predisposing syndrome 2015-03-30 criteria provided, single submitter clinical testing
Counsyl RCV000576870 SCV000677741 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000212842 SCV000149604 pathogenic not provided 2017-06-29 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.400C>T at the cDNA level and p.Arg134Ter (R134X) at the protein level. The substitution creates a nonsense variant, changing 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 the homozygous or compound heterozygous state in at least three young individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome and a history of caf? au lait spots, multiple cancers, and constitutional microsatellite instability (Hamilton 1995, De Vos 2004, Daou 2015, Lavoine 2015). A cell-line derived from one of the compound heterozygous patients displayed absent mismatch repair (MMR)-activity (Parsons 1995). PMS2 Arg134Ter has also been observed in the heterozygous state in several individuals with Lynch-related tumors showing isolated loss of PMS2 on tumor immunohistochemistry (Senter 2008, Vaughn 2013, Rosty 2016). We consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000576870 SCV000840047 pathogenic Hereditary nonpolyposis colorectal cancer type 4 2017-09-19 criteria provided, single submitter clinical testing The c.400C>T (p.R134*) variant in the PMS2 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with constitutional mismatch repair deficiency syndrome as well as in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 15077197, 18602922, 23012243, 26681312, 26895986). The c.400C>T (p.R134*) variant in the PMS2 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076872 SCV000918060 pathogenic Lynch syndrome 2018-07-13 criteria provided, single submitter clinical testing Variant summary: PMS2 c.400C>T (p.Arg134X) 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 (eg. c.697C>T, p.Gln233X; c.736_741delinsTGTGTGTGAAG, p.Pro246fsX3). The variant allele was found at a frequency of 8.2e-06 in 121392 control chromosomes. c.400C>T has been reported in the literature in individuals affected with Turcot syndrome who carry a second pathogenic variant (DeVos_2004) and in patients with Lynch Syndrome and colorectal cancer (Senter_2008, Durno_2005). These data indicate that the variant is likely to be associated with disease. Additionally, this variant was found to have a dominant negative effect in hamster fibroblast cells (Nicolaides_1998) but not in human fibroblast cells (Yamada_2003). However, the variant was found to abrogate the interaction with MLH1 (Nicolaides_1998), a known pathogenic mechanism. Six 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.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076872 SCV000108365 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524474 SCV000166386 pathogenic Hereditary nonpolyposis colon cancer 2018-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg134*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs63750871, ExAC 0.001%). This variant has been reported in the homozygous state and in trans with different pathogenic PMS2 variants in individuals with constitutional mismatch repair deficiency (CMMR-D) (PMID: 25850602, 15077197, 26318770). This variant has also been reported in individuals with colorectal cancer, Lynch syndrome and ovarian cancer (PMID: 18602922, 23012243, 26681312, 26895986). ClinVar contains an entry for this variant (Variation ID: 9234). While an experimental study has shown that this truncating variant does not decrease mismatch repair activity in a human fibroblast cell line (PMID: 12714694), two additional studies in patient-derived cell lines and a hamster cell line have shown that cells carrying this variant have impaired mismatch repair activity (PMID: 7632227, 9488480). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this change has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000076872 SCV000713220 pathogenic Lynch syndrome 2017-10-20 criteria provided, single submitter clinical testing The p.Arg134X variant in PMS2 has been reported in the heterozygous state in 5 f amilies (6 individuals) with Lynch syndrome-associated cancers (Parsons 1995, No rquist 2016, Rosty 2016) and in the compound heterozygous state in 2 families (3 individuals) with constitutional mismatch repair disease (CMMRD; De Vos 2004, L avoine 2015). In vitro functional studies provide some evidence that the p.Arg13 4X variant may decrease mismatch repair function resulting in microsatellite ins tability (Parsons 1995, Nicolaides 1998, Gibson 2006). This variant has also bee n identified in 1/126384 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs63750871). This nonsense var iant leads to a premature termination codon at position 134, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the P MS2 gene is an established disease mechanism in Lynch syndrome. In addition, thi s variant was classified as pathogenic on September 5, 2013 by the ClinGen-appro ved InSiGHT expert panel (SCV000108365.2). In summary, this variant meets criter ia to be classified as pathogenic for Lynch syndrome in an autosomal dominant ma nner, based upon predicted impact on the protein, presence in multiple affected individuals, very low frequency in the general population and functional evidenc e.
OMIM RCV000009815 SCV000030036 pathogenic Turcot syndrome 2004-05-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212842 SCV000889627 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing

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