ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1927C>T (p.Gln643Ter) (rs63751422)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164116 SCV000214731 pathogenic Hereditary cancer-predisposing syndrome 2017-05-24 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)
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735282 SCV000854435 pathogenic Pulmonary arterial hypertension; Respiratory insufficiency; Pulmonary insufficiency criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148733 SCV000190468 pathogenic Turcot syndrome 2014-06-01 no assertion criteria provided research
Color RCV000164116 SCV000686167 pathogenic Hereditary cancer-predisposing syndrome 2016-09-16 criteria provided, single submitter clinical testing
GeneDx RCV000223612 SCV000279560 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1927C>T at the cDNA level and p.Gln643Ter (Q643X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), 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 multiple individuals with colorectal cancer whose tumors lacked PMS2 expression on immunohistochemistry (Senter 2008, Goodenberger 2016, Rosty 2016). PMS2 Gln643Ter has also been observed in the compound heterozygous state in at least two individuals with constitutional mismatch repair deficiency syndrome, one of whom lacked PMS2 expression in both tumor and normal tissues (Agostini 2005, Vaughn 2010). We therefore consider PMS2 Gln643Ter to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076835 SCV000697317 pathogenic Lynch syndrome 2016-06-21 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1927C>T (p.Gln643X) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. Nonsense and frameshift muations down stream of this variant have been identified in CRC patients and classified as pathogenic (via HGMD and ClinVar: p.Q719*, p.L731*, p.Arg802*, p.Glu836*). IHC revealed that a patient who carried p.Gln643X and p.Lys413fs in trans showed PMS2 was absent, indicating that the c.1927C>T transcript is either undergoes non-sense mediated decay, or the protein product, Gln643X, is not stable. This variant was absent in 121400 control chromosomes, but has been reported in multiple affected individuals. Two reported patients were compound heterozygous with another PMS2 pathogenic variant (p.S46I or p.Lys413fs) in trans (Agostini_AJG_2005 and Pritchard_JMD_2012, respectively). Germline biallelic mutations in MMR genes result in early childhood cancer syndrome (CCS). This syndrome results from complete deficiency of MMR function and differs from HNPCC in the tumor spectrum and age of onset (Roy_Pediatric Blood Cancer_2009). Both patients were early onset with multiple cancers, thus the compound heterozygous genotype was consistent with the observed severe clinical phenotype in these patients. The variant of interest has also been observed in heterozygous state in CRC patients with a later age of onset than observed in compound heterozygotes (Senter_GastrEnt_2008 and Agostini_AJG_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076835 SCV000108322 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Invitae RCV000524452 SCV000261552 pathogenic Hereditary nonpolyposis colon cancer 2018-10-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln643*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Lynch syndrome (PMID: 18602922, 23012243, 20205264, 26895986), and with another pathogenic variant in PMS2 in an individual affected with constitutional mismatch repair deficiency syndrome (PMID: 16144131). ClinVar contains an entry for this variant (Variation ID: 91320). 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 RCV000076835 SCV000731326 pathogenic Lynch syndrome 2016-12-08 criteria provided, single submitter clinical testing The p.Gln643X variant in PMS2 has been identified in 4 individuals with PMS2-ass ociated cancers, including 2 individuals with multiple, early-onset cancers who also carried second, pathogenic variants in PMS2 (Agostini 2005, Senter 2008, Va ughn 2010, Rosty 2016). Furthermore, the variant segregated with colorectal canc er in 1 affected family member (Agostini 2005), and was absent from large popula tion studies. This nonsense variant leads to a premature termination codon at po sition 643, which is predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the PMS2 gene is an established disease mechanism for Lynch syndrome. Additionally, this variant was classified as Pathogenic on Septe mber 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108322. 2). In summary, the p.Gln643X variant meets criteria to be classified as pathoge nic for Lynch syndrome in an autosomal dominant manner.

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