ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.631C>T (p.Arg211Ter) (rs760228510)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222317 SCV000279402 pathogenic not provided 2017-09-25 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.631C>T at the cDNA level and p.Arg211Ter (R211X) 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 at least one individual with a personal history of colon cancer showing microsatellite instability and absent PMS2 protein via immunohistochemistry (Buchannan 2017). We consider this variant to be pathogenic.
Invitae RCV000473579 SCV000552000 pathogenic Hereditary nonpolyposis colon cancer 2019-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg211*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs760228510, ExAC 0.006%). This variant has been observed in an individual with Lynch syndrome (PMID: 27273229). ClinVar contains an entry for this variant (Variation ID: 234508). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000568505 SCV000670743 pathogenic Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000568505 SCV000686222 pathogenic Hereditary cancer-predisposing syndrome 2017-02-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001174885 SCV001338298 pathogenic Lynch syndrome 2020-02-13 criteria provided, single submitter clinical testing Variant summary: PMS2 c.631C>T (p.Arg211X) 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. The variant was absent in 251494 control chromosomes. c.631C>T has been reported in the literature in individuals affected with colorectal cancer, pancreatic ductal adenocarcinoma, or breast cancer (Jiang_2019, Buchanan_2016, Ohmoto_2018, Siraj_2017). These data indicate that the variant is likely to be associated with disease. Four 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.

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