ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.493-2A>G (rs587781784)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PTEN Variant Curation Expert Panel RCV000710293 SCV000840458 pathogenic PTEN hamartoma tumor syndrome 2017-10-18 reviewed by expert panel curation PTEN c.493-2A>G (IVS5-2A>G) 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). PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000222118.9) PM2: Absent in large sequenced populations.
Ambry Genetics RCV000130038 SCV000184864 pathogenic Hereditary cancer-predisposing syndrome 2016-06-16 criteria provided, single submitter clinical testing The c.493-2A>G pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the PTEN gene. This mutation was previously detected in an individual satisfying operational diagnostic criteria for Cowden syndrome (Ambry internal data). In addition, another alteration at this position, c.493-2A>C, was reported in a child with macrocephaly and hamartomatous GI polyposis by age 5 and classified as pathogenic (Tan WH et al. J. Med. Genet. 2007; 44:594-602). Based on the BDGP in silico splicing model, the c.493-2A>G mutation is predicted to abolish the native splice acceptor site. In addition to the clinical data summarized above, since alterations that disrupt the canonical splice acceptor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
GeneDx RCV000254682 SCV000222118 pathogenic not provided 2018-11-23 criteria provided, single submitter clinical testing The c.493-2 A>G splice site variant in the PTEN gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant destroys the canonical splice acceptor site in intron 5, and is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Additionally, a different nucleotide substitution at the same position (c.493-2 A>C) has been reported previously in a patient with PTEN-hamartoma tumor syndrome (Tan et al., 2007). Based on currently available evidence, we consider c.493-2A>G to be pathogenic.
Invitae RCV000710293 SCV000936765 pathogenic PTEN hamartoma tumor syndrome 2019-11-10 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 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 observed in an individual affected with Cowden syndrome (PMID: 28677221). ClinVar contains an entry for this variant (Variation ID: 141485). Experimental studies have shown that this variant results in skipping of exon 6 of the PTEN mRNA (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.
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000515821 SCV000579234 pathogenic Cowden syndrome 1 2017-05-26 no assertion criteria provided research

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