rs587782455

Variant names:

• chr10-87960892-A-G
• rs587782455
• NM_000314.8:c.802-2A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-87960892-A-G
• chr10-87960892-A-T

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.802-2A>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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.81

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 0.18564357 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 43, new splice context is: aaatacattcttcataccAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87960892-A-G is Pathogenic according to our data. Variant chr10-87960892-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 189509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960892-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.802-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1321-2A>G		splice_acceptor_variant, intron_variant	Intron 8 of 9		NP_001291646.4
PTEN	NM_001304718.2	c.211-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 8		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.802-2A>G		splice_acceptor_variant, intron_variant	Intron 7 of 8	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000173 AC: 2 AN: 1156364 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 577792

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000465

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000113

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

May 26, 2017

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

May 10, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 28013114]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. -

PTEN hamartoma tumor syndrome Pathogenic:2

Feb 17, 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 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 27477328, 28677221). ClinVar contains an entry for this variant (Variation ID: 189509). 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. -

Apr 02, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802-2A>G variant in PTEN has been reported in 1 individual with Cowden syndrome (a sub-type of PTEN hamartoma tumor syndrome; Chen 2017) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Functional studies suggest that the variant causes altered splicing leading to an abnormal or absent protein (Chen 2017). Heterozygous loss-of-function of the PTEN gene is an established disease mechanism in individuals with PTEN hamartoma tumor syndrome. In summary, this variant is pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PM2; PP4. -

not provided Pathogenic:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PTEN: PVS1, PM2, PS3:Supporting, PS4:Supporting -

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 in the PTEN gene. This variant has been reported in individuals diagnosed with Cowden syndrome (Chen HH et al. J. Allergy Clin. Immunol., 2017 02;139:607-620.e15; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). In addition, RNA studies have demonstrated that this variant results in abnormal splicing with out-of-frame deletion of 43 nucleotides from the beginning of coding exon 8 through use of a cryptic acceptor site (Ambry internal data; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). A different pathogenic mutation at the same nucleotide position, c.802-2A>T, has been identified in individuals diagnosed with Cowden syndrome and results in the same splicing defect (Ambry internal data; 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). 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. -

Cowden syndrome Pathogenic:1

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PTEN c.802-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of PTEN function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Chen_2017). The variant was absent in 177630 control chromosomes (gnomAD). c.802-2A>G has been reported in the literature in multiple individuals affected with Cowden Syndrome (Chen_2017, Johnston_JHG_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 27477328, 35534676). ClinVar contains an entry for this variant (Variation ID: 189509). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.1

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		0.87		Position offset: 45
DS_AL_spliceai		1.0		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: rs587782455; hg19: chr10-89720649; COSMIC: COSV64301847;