ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1027-2A>G (rs1085308041)

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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 RCV000490606 SCV000579260 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491514 SCV000580037 pathogenic Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing Other data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Well-characterized mutation at same position;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Other strong data supporting pathogenic classification
GeneDx RCV000522568 SCV000616843 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing The c.1027-2A>G variant in the PTEN gene has been reported previously in an individual with macrocephaly, developmental delay, and penile freckling and in association with Cowden syndrome and Lhermite-Duclos Disease (Varga et al., 2009; Peiro et al., 2009; Negoro et al., 2000; Klisch et al., 2001). This splice site variant destroys the canonical splice acceptor site in intron 8. It 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. The c.1027-2A>G variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1027-2A>G as a pathogenic variant.
Invitae RCV000490606 SCV000766809 pathogenic PTEN hamartoma tumor syndrome 2019-06-12 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). Variants at this splice site have been observed in several individuals affected with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease (PMID: 28526761, 11052475, 27477328, 19265751, 19968660, Invitae). This variant is also known as IVS8-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 427581). 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.
Color RCV000491514 SCV001347411 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing

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