rs398123318

Positions:

• chr10-87925557-TGTAA-T

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 NM_000314.8 splice_donor, splice_donor_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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.209+4_209+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.728+4_728+7del		splice_donor_variant, splice_donor_region_variant, intron_variant
PTEN	NM_001304718.2	c.-540-5485_-540-5482del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.209+4_209+7del		splice_donor_variant, splice_donor_region_variant, intron_variant		1	NM_000314.8	P1

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, 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) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 11, 2023	This variant is not present in population databases (gnomAD no frequency). 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 has been observed in individual(s) with PTEN-related conditions (PMID: 10920277, 21103832; Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 92816). -

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

Mar 02, 2020

Published functional studies demonstrate a damaging effect: exon 3 skipping (Chen 2017); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; Chen HJ et al. (2017) Hum Mutat 38 (10):1372-1377 (PMID: 28677221); Barreras P et al. (2016) Spine J (PMID: 26795104); Bae BG et al. (2011) Acta dermato-venereologica 91 (1):88-90 (PMID: 21103832); This variant is associated with the following publications: (PMID: 28677221, 26795104, 21103832, 10920277) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 12, 2015

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. 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 (Agrawal S et al. Hum. Mol. Genet. 2005 Aug; 14(16):2459-68). Based on the available evidence, c.209+4_209+7delAGTA is classified as a pathogenic 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;