ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.209+4_209+7del (rs398123318)

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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 RCV000645064 SCV000840483 pathogenic PTEN hamartoma tumor syndrome 2017-12-18 reviewed by expert panel curation PTEN c.209+4_209+7delAGTA (IVS3+4_IVS3+7delAGTA) 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). PS3: RNA, mini-gene, or other assay shows impact on splicing. (PMID 28677221) 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)) PM2: Absent in large sequenced populations (PMID 27535533). PP1_M: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (Internal laboratory contributor(s)) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 28677221, internal laboratory contributor(s) SCV000273868.4)
Ambry Genetics RCV000217746 SCV000273868 pathogenic Hereditary cancer-predisposing syndrome 2015-02-12 criteria provided, single submitter clinical testing The c.209+4_209+7delAGTA intronic pathogenic mutation, located in intron 3 of the PTEN gene, results from a deletion of 4 nucleotides within intron 3 of the PTEN gene.<span style="background-color: initial;">In one study, this variant was detected in an individual with palmar keratoses, papillary thyroid cancer, thyroid adenomatous hyperplasias, and vascular anomalies (cutaneous hemangioma and cervical paraspinal arterial venous malformation). Results of mRNA sequencing showed a single amino acid substitution in the first codon of exon 3 (R55S) with transcriptional skipping of the remainder of exon 3 (loss of amino acids 56-70) (Bae BG et al. Acta Derm. Venereol. 2011 Jan; 91(1):88-90). Skipping of exon 3 has been shown to markedly reduce protein phosphatase activity (<span style="background-color: initial;">Agrawal S et al. Hum. Mol. Genet. 2005 Aug; 14(16):2459-68).<span style="background-color: initial;">Based on the available evidence,<span style="background-color: initial;">c.209+4_209+7delAGTA<span style="background-color: initial;">is classified as a pathogenic mutation.
Invitae RCV000645064 SCV000766805 pathogenic PTEN hamartoma tumor syndrome 2019-12-22 criteria provided, single submitter clinical testing This sequence change falls in intron 3 of the PTEN gene. It does not directly change the encoded amino acid sequence of the PTEN protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with, or having features consistent with, PTEN-related conditions, including a de novo observation (PMID: 10920277, 21103832, Invitae). This variant is also known as 209+1delGTAA in the literature. ClinVar contains an entry for this variant (Variation ID: 92816). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Analysis of patient lymphocyte mRNA has shown that this variant causes aberrant splicing, resulting in skipping of exon 3 and a loss of 15 amino acid residues from the PTEN protein (PMID: 21103832). For these reasons, this variant has been classified as Pathogenic.
Cancer Genomic Medicine Translational Research Lab,Cleveland Clinic Genomic Medicine Institute RCV000515898 SCV000579226 pathogenic Cowden syndrome 1 2017-05-26 no assertion criteria provided research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785586 SCV000924161 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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