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 The c.1027-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the PTEN gene. This mutation was first described in a 9-month-old male with developmental delay, and was also detected in his father, who had a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Varga EA et al. Genet. Med. 2009 Feb; 11(2):111-7). This mutation has also been described in a patient with synchronous bilateral breast cancer, benign trichilemmoma, oral mucosal papilomatosis, and acral keratoses (Peir&oacute; G et al. Breast J. 2010;16(1):77-81). In one laboratory analysis, this mutation was detected in 1/802 samples submitted for clinical PTEN testing (Pilarski R et al. J. Med. Genet. 2011 Aug; 48(8):505-12). Another pathogenic alteration at the same nucleotide position (c.1027-2A>C) has also been described in an individual with Cowden syndrome (Tan MH et al. Am J Hum Genet. 2011;88(1):42-56). This alteration is also known as IVS8-2A>G in published literature. <span style="background-color:initial">Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site; however, direct evidence is unavailable. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.​<span style="background-color:initial">
GeneDx RCV000522568 SCV000616843 pathogenic not provided 2021-02-25 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing and disrupt the critical C2 domain, although in the absence of functional evidence the actual effect of this sequence change is unknown (Wang 2008); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11337322, 12015762, 11052475, 19968660, 19265751, 21659347, 23319441, 27477328, 28526761, 14655763, 28152038, 18626510)
Invitae RCV000490606 SCV000766809 pathogenic PTEN hamartoma tumor syndrome 2020-07-13 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 Health, Inc RCV000491514 SCV001347411 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing

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