ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1027-1G>A (rs1057517809)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491449 SCV000580074 pathogenic Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
ClinGen PTEN Variant Curation Expert Panel RCV000690306 SCV000930125 pathogenic PTEN hamartoma tumor syndrome 2019-06-25 reviewed by expert panel curation PTEN c.1027-1G>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 (PMID 30311380). 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). PM2: Absent in large sequenced populations (PMID 27535533). PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor SCV000490754.2)
GeneDx RCV000414617 SCV000490754 pathogenic not provided 2015-07-09 criteria provided, single submitter clinical testing The c.1027-1 G>A splice site variant in the PTEN gene has not been previously published as a germline variant to our knowledge, but has been previously reported in association with primary endometrial carcinoma (Rudd et al. 2011). This variant destroys the canonical splice acceptor site in intron 8, and is expected to cause abnormal gene splicing. Therefore, we interpret c.1027-1 as a pathogenic variant.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785587 SCV000924162 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000690306 SCV000817988 pathogenic PTEN hamartoma tumor syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change affects an acceptor 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). This variant has been observed to segregate with PTEN-related disease in one family (Invitae) and has been observed in individuals affected with Cowden syndrome (PMID: 27477328). ClinVar contains an entry for this variant (Variation ID: 372482). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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