ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1026+1G>A (rs786201041)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162423 SCV000212764 likely pathogenic Hereditary cancer-predisposing syndrome 2014-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000515989 SCV000579244 pathogenic Cowden syndrome 1 2017-05-26 no assertion criteria provided research
ClinGen PTEN Variant Curation Expert Panel RCV000710314 SCV000840497 pathogenic PTEN hamartoma tumor syndrome 2017-10-18 reviewed by expert panel curation PTEN c.1026+1G>A (IVS8+1G>A) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4) (PMID 28677221). PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4)
Invitae RCV000710314 SCV000951411 pathogenic PTEN hamartoma tumor syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 8) of the PTEN gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individuals affected with Cowden or Cowden-like syndrome, and shown to segregate with disease in a family (PMID: 28677221, 21194675). This variant is also known as IVS8+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 183722). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this nucleotide change causes alternative splicing, however, the resulting transcript has been described as a natural isoform of PTEN (PMID: 28677221). In another study, no effect on splicing was detected (PMID: 16014636). The clinical significance of these studies is uncertain. For these reasons, this variant has been classified as Pathogenic.

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