ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1076dup (p.Leu359fs) (rs267608156)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076794 SCV000108276 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000569722 SCV000676163 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Integrated Genetics/Laboratory Corporation of America RCV000076794 SCV000697277 likely pathogenic Lynch syndrome 2016-04-15 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1076dupT variant results in a frameshift, , which alters the proteins amino acid sequence beginning at position 359 and leads to a premature termination codon five amino acids downstream. It is predicted to cause a truncated or absent protein product, which is are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Ile611fs). Mutation Taster predicts a damaging outcome for this variant, but there were no published functional studies on this variant at the time of classification. This variant is not found in 121382 control chromosomes, but has been identified in at least 2 cancer patients (1 patient with endometrial cancer and cecum cancer and 1 with ascending colon cancer). In addition, a clinical laboratory classified this variant as pathogenic without evidence to independently evaluate. Taken together, this variant was classified as likely pathogenic until additional information is available.
Invitae RCV000629951 SCV000750907 pathogenic Hereditary nonpolyposis colon cancer 2018-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu359Phefs*6) 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). ClinVar contains an entry for this variant (Variation ID: 91289). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000657182 SCV000778903 pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing This duplication of one nucleotide in PMS2 is denoted c.1076dupT at the cDNA level and p.Leu359PhefsX6 (L359FfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TCTT[dupT]GATA. The duplication causes a frameshift which changes a Leucine to a Phenylalanine at codon 359, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PMS2 c.1076dupT has been observed in at least three individuals with a personal history of colon and/or endometrial cancer (Senter 2008, Goodenberger 2016). We consider this variant to be pathogenic.
Color RCV000569722 SCV000905474 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657182 SCV001249107 pathogenic not provided 2018-09-01 criteria provided, single submitter clinical testing

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