rs1114167621

chr10-87931045-G-Achr10-87931045-G-Cchr10-87931045-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.210-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.13

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 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.017739274 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 42, new splice context is: accgccaaatttaattgcAGagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 10-87931045-G-A is Pathogenic according to our data. Variant chr10-87931045-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 427616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.210-1G>A		splice_acceptor_variant		ENST00000371953.8
PTEN	NM_001304717.5	c.729-1G>A		splice_acceptor_variant
PTEN	NM_001304718.2	c.-540-1G>A		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.210-1G>A		splice_acceptor_variant		1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 12, 2021	- -
Pathogenic, no assertion criteria provided	research	Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	May 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 14, 2024	This variant is considered 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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28677221, 11071384, 22381246, 16014636, 32162695]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221, 11071384, 16014636]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2023	Observed in multiple individuals with PTEN hamartoma tumor syndrome (Celebi et al., 2000; Mester et al., 2012; Ngeow et al., 2012; Chen et al., 2017); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21956414, 20600018, 28677221, 23066114, 21194675, 16014636, 26228616, 22381246, 11071384, 32162695, 30787465, 35241692) -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2021

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (PMID: 11071384, 16014636, 28677221). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 427616). This variant is also known as IVS3-1G>A. Disruption of this splice site has been observed in individuals with clinical features of Cowden syndrome (PMID: 11071384, 16014636, 21956414, 28677221, 32162695). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2023

The c.210-1G>A intronic pathogenic mutation, results from a G to A one nucleotide upstream from coding exon 4 of the PTEN gene. This mutation has been reported in multiple individuals with classic Cowden syndrome and Cowden Syndrome-like features (Celebi JT et al. Hum. Genet. 2000 Sep; 107(3):234-8; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec; 96(12):E2063-71; Chen HJ et al. Hum. Mutat. 2017 10;38(10):1372-1377; Heald B et al. Gastroenterology 2010 Dec;139(6):1927-33; Mester J et al. Urology 2012 May;79(5):1187.e1-7; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43; Yehia L et al. NPJ Genom Med, 2022 Mar;7:16). In addition, RNA studies performed have shown that this mutation results in out-of-frame skipping of coding exon 4 with a predicted premature termination codon in coding exon 5 (Ambry internal data; Celebi JT et al. Hum. Genet. 2000 Sep;107(3):234-8; Chen HJ et al. Hum. Mutat. 2017 10;38(10):1372-1377; Agrawal S et al. Hum Mol Genet, 2005 Aug;14:2459-68). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	34
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 13
DS_AL_spliceai		1.0		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: rs1114167621; hg19: chr10-89690802; COSMIC: COSV64288901;