rs786201041

Positions:

• chr10-87961119-G-A
• chr10-87961119-G-C
• chr10-87961119-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PVS1 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: PTEN c.1026+1G>A (IVS8+1G>A) 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).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4) (PMID 28677221).PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000103/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 9.47

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]

PTEN (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1026+1G>A		splice_donor_variant, intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1545+1G>A		splice_donor_variant, intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.435+1G>A		splice_donor_variant, intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1026+1G>A		splice_donor_variant, intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2024	Canonical splice site variant demonstrated to result in an abnormal protein product, disrupting the critical C2 domain (PMID: 18626510, 28677221); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15372512, 21194675, 28677221, 30311380, 18626510, 36131570, 34386506, 29891884, 31263500, 35931053, 36746884) -
not provided, no classification provided	in vivo	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 15, 2017	- -

Cowden syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 09, 2023	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -
Pathogenic, no assertion criteria provided	research	Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	May 26, 2017	- -

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2021	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). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 28677221; Invitae). ClinVar contains an entry for this variant (Variation ID: 183722). This variant is also known as IVS8+1G>A. Disruption of this splice site has been observed in individuals with Cowden or Cowden-like syndrome (PMID: 21194675, 28677221). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the PTEN gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	PTEN c.1026+1G>A (IVS8+1G>A) 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4) (PMID 28677221). PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 28677221, internal laboratory contributor(s) SCV000212764.4) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2024

The c.1026+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the PTEN gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This mutation has been reported in multiple individuals meeting clinical criteria for Cowden syndrome (Agrawal S et al. Hum Mol Genet. 2005 Aug;14(16):2459-68; Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377; Ambry internal data). In one study, RNA analysis showed that this variant led to abnormal splicing, with retention of 190 nucleotides from intron 8 and introduction of a stop codon at p.345, that would result in loss of amino acids encompassing exon 9 (Chen HJ et al. Hum Mutat, 2017 10;38:1372-1377). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786201041; hg19: chr10-89720876; COSMIC: COSV64288702;