ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1261C>T (p.Arg421Ter) (rs587778617)

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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) RCV000076804 SCV000108286 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000076804 SCV000271438 pathogenic Lynch syndrome 2016-03-03 criteria provided, single submitter clinical testing The p.Arg421X variant in PMS2 has been reported in one carrier with unspecified phenotype (Suerink 2015), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 421, which is p redicted to lead to a truncated or absent protein. Heterozygous loss of function of the PMS2 gene is an established disease mechanism in Lynch syndrome. In summ ary, this variant meets our criteria to be classified as pathogenic for Lynch sy ndrome in an autosomal dominant manner based upon the predicted impact to the pr otein.
Ambry Genetics RCV000223405 SCV000276002 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 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)
GeneDx RCV000219846 SCV000279393 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted PMS2 c.1261C>T at the cDNA level and p.Arg421Ter (R421X) 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 observed in at least two individuals with suspected Lynch Syndrome (Vaughn 2013, Suerink 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on current information, we consider this variant to be pathogenic.
Invitae RCV000627692 SCV000285057 pathogenic Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg421*) 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 with colorectal cancer and/or suspected Lynch syndrome (PMID: 23012243, 26110232). ClinVar contains an entry for this variant (Variation ID: 91299). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000076804 SCV000592931 pathogenic Lynch syndrome 2015-01-13 criteria provided, single submitter clinical testing
GeneKor MSA RCV000223405 SCV000821766 pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000121843 SCV000086041 not provided not specified 2013-09-19 no assertion provided reference population
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000786880 SCV000925779 likely pathogenic Hereditary nonpolyposis colorectal cancer type 4 2018-09-27 no assertion criteria provided clinical testing

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