chr10-87933147-C-G

Variant names:

• chr10-87933147-C-G
• rs121909224
• NM_000314.8:c.388C>G
• PTEN p.Arg130Gly

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 23 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.388C>G (p.Arg130Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000930114: Phosphatase activity <50% of wild type (PMID 10866302, PMID 21828076, PMID 29706350)" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R130L: Pathogenic/Likely_pathogenic (ClinVar VariationId 376509, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R130?: Uncertain_significance (ClinVar VariationId 2687576, 0 stars); p.R130?: Uncertain_significance (ClinVar VariationId 2687578, 0 stars); p.R130= (synonymous): Benign/Likely_benign (ClinVar VariationId 1735874, 2 stars); p.R130= (synonymous): Benign/Likely_benign (ClinVar VariationId 3903832, 2 stars); p.R130= (synonymous): Likely_benign (ClinVar VariationId 1648484, 1 star) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 239 samples carry this exact amino acid change out of 1912 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 5.57
• Publications: 298 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Lhermitte-Duclos disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PTEN are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 23 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000930114: Phosphatase activity <50% of wild type (PMID 10866302, PMID 21828076, PMID 29706350); SCV002142648: Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 11948419, 21828076, 24292679).; SCV002032654: Published functional studies demonstrate a damaging effect: loss of phosphatase activity, decreased protein expression, and nuclear mislocalization (Han et al., 2000; Koul et al., 2002; He et al., 2011; Rodriguez-Escudero et al., 2011; Nguyen et al., 2014; Papa et al., 2014); SCV004188780: Functional studies indicate this variant impacts protein function [PMID: 10866302,11051241, 20926450].; SCV005158317: In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am. J. Hum. Genet. 2018 05;102:943-955). This variant also demonstrated wild type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In other assays testing PTEN function, this variant showed functionally abnormal results (Lobo GP et al. Hum Mol Genet, 2009 Aug;18:2851-62; He X et al. Hum Mol Genet, 2011 Jan;20:80-9; Rodr&iacute;guez-Escudero I et al. Hum Mol Genet, 2011 Nov;20:4132-42).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 54 pathogenic, 0 benign (OR vs. background: 545.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000104 by highest known P/LP ClinVar AF 0.000104) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R130L: Pathogenic/Likely_pathogenic (ClinVar VariationId 376509, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R130?: Uncertain_significance (ClinVar VariationId 2687576, 0 stars); p.R130?: Uncertain_significance (ClinVar VariationId 2687578, 0 stars); p.R130= (synonymous): Benign/Likely_benign (ClinVar VariationId 1735874, 2 stars); p.R130= (synonymous): Benign/Likely_benign (ClinVar VariationId 3903832, 2 stars); p.R130= (synonymous): Likely_benign (ClinVar VariationId 1648484, 1 star)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 4.120). ClinVar shows strong pathogenic missense enrichment: 365 P/LP and 36 B/LB missense entries (ratio 10.1×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTEN NM_000314.8	MANE Select	c.388C>G p.Arg130Gly	missense	Exon 5 of 9	Prot: NP_000305.3
	PTEN NM_001304717.5		c.907C>G p.Arg303Gly	missense	Exon 6 of 10	Prot: NP_001291646.4
	PTEN NM_001304718.2		c.-363C>G	5_prime_UTR	Exon 4 of 9	Prot: NP_001291647.1

PTEN NM_000314.8

MANE Select

HGVSc / HGVSpc.388C>Gp.Arg130Gly

Exon rankExon 5 of 9

missense

Prot: NP_000305.3

PTEN NM_001304717.5

HGVSc / HGVSpc.907C>Gp.Arg303Gly

Exon rankExon 6 of 10

missense

Prot: NP_001291646.4

PTEN NM_001304718.2

HGVSc / HGVSpc.-363C>G

Exon rankExon 4 of 9

5_prime_UTR

Prot: NP_001291647.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTEN ENST00000371953.8	TSL:1MANE Select	c.388C>G p.Arg130Gly	missense	Exon 5 of 9	Prot: ENSP00000361021.3 UniProt:
	PTEN ENST00000693560.1		c.907C>G p.Arg303Gly	missense	Exon 6 of 10	Prot: ENSP00000509861.1 UniProt:
	PTEN ENST00000700029.2		c.388C>G p.Arg130Gly	missense	Exon 5 of 10	Prot: ENSP00000514759.2 UniProt:

PTEN ENST00000371953.8

TSL:1MANE Select

HGVSc / HGVSpc.388C>Gp.Arg130Gly

Exon rankExon 5 of 9

missense

Prot: ENSP00000361021.3UniProt: P60484-1

PTEN ENST00000693560.1

HGVSc / HGVSpc.907C>Gp.Arg303Gly

Exon rankExon 6 of 10

missense

Prot: ENSP00000509861.1UniProt: P60484-2A0A8I5KSF9

PTEN ENST00000700029.2

HGVSc / HGVSpc.388C>Gp.Arg130Gly

Exon rankExon 5 of 10

missense

Prot: ENSP00000514759.2UniProt: A0A8V8TPK6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Cowden syndrome 1 (2)
2	-	-	PTEN hamartoma tumor syndrome (2)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
-	-	-	Neoplasm (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	35
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-9.8
GPN-Star score	N/A	9.8
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.2	H
PhyloP100	Uncertain	5.6
popEVE	Pathogenic	-6.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	1.0
VESM-3B	Benign	-16

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 abnormal (RUO)

1 normal

2 no calibration

4 assays found for this variant.

Clinical calibration: 0 functionally abnormal (PS3), 1 functionally normal (BS3).

Research-use-only (RUO) calibration: 1 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 2 assays (score only).

RUO results are not validated; give them no weight next to the clinical ones.

Protein level

PTEN VAMP-seq

• Gene: PTEN
• Assay type: Reporter
• Mechanism: Regulation of protein stability
• Model system: Immortalized human cells (Homo sapiens)
• Score: 1.09 · p.Arg130Gly (assay numbering)

Classified as

BS3 supportingFunctionally normalIGVF Coding Variant Focus Group -- Controls: All Variants: wt-like

+2 more calibrations

BS3 moderateFunctionally normalRUO ExCALIBR calibration (ClinVar 2018): BS3 Moderate (-2)

BS3 supportingFunctionally normalRUO ExCALIBR calibration: BS3 Supporting (-1)

Nucleotide level

PTEN lipid phosphatase scores

PTEN Lipid Phosphatase

• Gene: PTEN
• Assay type: Cell fitness
• Mechanism: Catalytic and Lipid phosphatase activity
• Model system: Yeast (Saccharomyces cerevisiae)
• Score: -2.14 · p.Arg130Gly (assay numbering)

Classified as

No clinical calibration. Only research-use-only (RUO) calibrations exist for this assay — they are not reliable evidence; treat them with extreme caution.

PS3 strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Strong (4)

+1 more calibration

PS3 moderateFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate (2)

Protein level

PTEN VAMP-seq Fill-in

• Gene: PTEN
• Score: 1.23 · p.Arg130Gly (assay numbering)

No calibration data

This score is at approximately the 87th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

PTEN VAMP-seq Combined

Meta-analysis of urn:mavedb:00000013-a-1, urn:mavedb:00000101-a-1

• Gene: PTEN
• Score: 1.12 · p.Arg130Gly (assay numbering)

No calibration data

This score is at approximately the 93th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs121909224;

hg19: chr10-89692904;

COSMIC: COSV64288384;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar