10-87965285-A-G

Variant names:

• chr10-87965285-A-G
• rs1085308041
• NM_000314.8:c.1027-2A>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.1027-2A>G variant causes a splice acceptor, intron 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.90

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 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 5.4818482 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.6, offset of 6, new splice context is: ttttctttctctgggtgaAGctg. 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
• PP5: Variant 10-87965285-A-G is Pathogenic according to our data. Variant chr10-87965285-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87965285-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1027-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1546-2A>G		splice_acceptor_variant, intron_variant	Intron 9 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.436-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1027-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:4

Nov 03, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and Lhermitte-Duclos disease (PMID: 11052475, 19265751, 19968660, 27477328, 28526761; Invitae). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 427581). 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. -

Mar 01, 2017

Herman Laboratory, Nationwide Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1027-2A>G variant in the PTEN gene is expected to disrupt the splicing acceptor site in intron 8 (SpliceAI, delta score = 0.99), and is expected to alter RNA splicing, leading to disrupted protein structure and function. Disruption of this splice site is also known as IVS8-2A>G in the early literature. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has been observed in individuals with PTEN hamartoma tumor syndrome (PHTS), macrocephaly, developmental delay, Cowden syndrome, and Lhermitte-Duclos disease (PMID: 11052475, 19265751, 19968660, 21659347, 27477328, 28526761, 32190315, 21659347, 21194675). Other variants affecting the same splicing locus, c.1027-2A>C, c.1027-1G>C, and c.1027-1G>A, have been reported as pathogenic in ClinVar. In addition, this variant is absent in the general population database according to gnomAD. Therefore, the c.1027-2A>G variant in the PTEN gene has been classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 17, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1027-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the PTEN gene. This alteration was first described in a 9-month-old male with developmental delay, and was also detected in his father, who had a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Varga EA et al. Genet. Med. 2009 Feb; 11(2):111-7). This alteration has also been described in a patient with synchronous bilateral breast cancer, benign trichilemmoma, oral mucosal papillomatosis, and acral keratoses (Peiró G et al. Breast J. 2010;16(1):77-81). In one laboratory analysis, this alteration was detected in 1/802 samples submitted for clinical PTEN testing (Pilarski R et al. J. Med. Genet. 2011 Aug; 48(8):505-12). Another pathogenic alteration at the same nucleotide position (c.1027-2A>C) has also been described in an individual with Cowden syndrome (Tan MH et al. Am J Hum Genet. 2011;88(1):42-56). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is also known as IVS8-2A>G in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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. -

Apr 28, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the PTEN gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has been reported in individuals affected with macrocephaly, developmental delay, Cowden syndrome, Lhermitte-Duclos disease, and breast cancer (PMID: 11052475, 19265751, 19968660, 21659347, 27477328, 28526761, 32190315). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PTEN function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cowden syndrome 1 Pathogenic:1

Oct 09, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19265751, 27477328, 11052475, 21659347, 19968660]. -

not provided Pathogenic:1

Feb 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant expected to result in aberrant splicing and disrupt the critical C2 domain, although in the absence of functional evidence the actual effect of this sequence change is unknown (Wang 2008); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11337322, 12015762, 11052475, 19968660, 19265751, 21659347, 23319441, 27477328, 28526761, 14655763, 28152038, 18626510) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.3

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_AL_spliceai		0.99		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085308041; hg19: chr10-89725042; COSMIC: COSV64293079; COSMIC: COSV64293079;