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

Total submissions: 5

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