rs398123318

Variant names:

• chr10-87925557-TGTAA-T
• rs398123318
• NM_000314.8:c.209+4_209+7delAGTA

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS3 PP1_Moderate PM2 PM6_Strong PS4_Supporting

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: Genomes: not found (cov: 32)
• Consequence: PTEN ENST00000371953.8 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.29

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.209+1_209+4delGTAA		splice_donor_variant, splice_region_variant, intron_variant	Intron 3 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2024	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. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Dec 18, 2017	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

Pathogenic, no assertion criteria provided

research

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

May 26, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

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

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123318; hg19: chr10-89685314;