ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.165-2A>G (rs1085308043)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Herman Laboratory,Nationwide Children's Hospital RCV000490612 SCV000579263 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
GeneDx RCV000657856 SCV000779614 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing This variant is denoted PTEN c.165-2A>G or IVS2-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 2 of the PTEN gene. Splicing assays have demonstrated that this variant leads to use of a cryptic splice acceptor site, creating a frameshift (Chen 2017). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or an abnormal protein product. PTEN c.165-2A>G has been reported in several individuals with features of PTEN Hamartoma Tumor syndrome, with at least one de novo occurrence (Marsh 1998, Chen 2017, Hansen-Kiss 2017). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000490612 SCV000835296 pathogenic PTEN hamartoma tumor syndrome 2018-03-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 of the PTEN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Bannayan-Riley-Ruvalcaba syndrome (PMID: 28526761), and in families with Cowden disease (PMID: 9467011, 28677221). This variant is also known as IVS2-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 427584). An experimental study using mRNA from an affected individual has shown that this sequence change creates a new splice site that results in a frameshift (Phe56Valfs*7) and premature transcript termination (PMID: 28677221). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001012591 SCV001173063 pathogenic Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing 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;Functionally-validated splicing mutation
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000516092 SCV000579239 pathogenic Cowden syndrome 1 2017-05-26 no assertion criteria provided research

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