rs398123318
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM6_StrongPS4_SupportingPS3PP1_ModeratePM2
This summary comes from the ClinGen Evidence Repository: 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) LINK:https://erepo.genome.network/evrepo/ui/classification/CA220637/MONDO:0017623/003
Frequency
Consequence
ENST00000371953.8 splice_donor, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.209+4_209+7delAGTA | splice_region_variant, intron_variant | Intron 3 of 8 | ENST00000371953.8 | NP_000305.3 | ||
| PTEN | NM_001304717.5 | c.728+4_728+7delAGTA | splice_region_variant, intron_variant | Intron 4 of 9 | NP_001291646.4 | |||
| PTEN | NM_001304718.2 | c.-541-5485_-541-5482delAGTA | intron_variant | Intron 2 of 8 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2
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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with PTEN-related conditions (PMID: 10920277, 21103832; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 92816). Variants that disrupt 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. For these reasons, this variant has been classified as Pathogenic. -
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) -
Cowden syndrome 1 Pathogenic:1
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not provided Pathogenic:1
Identified in patients with features of PTEN Hamartoma Tumor syndrome referred for genetic testing at GeneDx and in published literature, segregating with disease in affected families (PMID: 26795104, 21103832, 28677221); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32782288, 10920277, 26795104, 21103832, 29152901, 28677221, 34897210, 12938083, 36453251, 31645350, 30311380, 24475377, 19457929, 16014636) -
Hereditary cancer-predisposing syndrome Pathogenic:1
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. This variant was reported in multiple individuals with features consistent with Cowden syndrome (Bae BG et al. Acta Derm. Venereol. 2011 Jan; 91(1):88-90; Balci TB et al. Am J Med Genet B Neuropsychiatr Genet, 2018 Jan;177:101-109; (Wang X et al. Am J Med Genet A, 2023 Mar;191:753-759). This alteration caused exon 3 skipping in the PTEN mRNA transcript (Agrawal S et al. Hum. Mol. Genet. 2005 Aug; 14(16):2459-68; Bae BG et al. Acta Derm. Venereol. 2011 Jan; 91(1):88-90; Chen HJ et al. Hum Mutat, 2017 Oct;38:1372-1377). This nucleotide region is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Ovarian neoplasm Pathogenic:1
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Endometrial carcinoma Pathogenic:1
The PTEN c.209+4_209+7del variant was identified in 2 of 146 proband chromosomes (frequency: 0.01) from individuals or families with Cowden syndrome (Chen 2017, Sawada 2000). The variant was identified in two case reports in individuals with Cowden syndrome (Bae 2011, Barreras 2018). This variant is also known as 209+1delGTAA in the literature. It was identified in dbSNP (ID: rs398123318) as "With Pathogenic allele", in ClinVar (3x as Pathogenic by Ambry Genetics, ClinGen PTEN variant curation expert panel and one other laboratory, 1x as Likely pathogenic by Invitae) and the LOVD 3.0 database. It was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). PTEN mRNA from patient derived cell lines demonstrated that the c. 209+4_209+7del variant causes exon 3 skipping. Western blot analysis revealed that in general intronic variants in PTEN that result in a altered splicing had decreased PTEN protein expression by half compared to variants that resulted in no splice changes however specific data for the c. 209+4_209+7del variant was not provided (Chen 2017). Skipping of exon 3 of the PTEN gene is predicted to cause and in-frame deletion of amino acids 56-70 and a single amino acid substitution of the arginine at position 55 to a serine (Bae 2011). The c.209+4_209+7del variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 3 of 3 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE) predict a greater than 10% difference in splicing. In summary, based on the above information this variant is classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at