10-87933147-C-T

Variant names:

• chr10-87933147-C-T
• rs121909224
• NM_000314.8:c.388C>T
• PTEN p.Arg130*

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 19 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO2_Very_StrongO3_SupportingO4_ModerateO7_Strong

The NM_000314.8(PTEN):c.388C>T (p.Arg130*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The gene PTEN is a tumor suppressor gene (CancerMine: 876 TSG, 281 oncogene, 265 driver citations). The gene PTEN is a known oncogene (CancerMine: 876 TSG, 281 oncogene, 265 driver citations). The gene PTEN is a cancer driver gene (CancerMine: 876 TSG, 281 oncogene, 265 driver citations). The variant allele was found at a cumulative frequency of 0.00000274 (AC=4) in the gnomAD database across 1,461,670 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (BayesDel (noAF)) 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 (★★). 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. The variant has been observed in cBioPortal in 540 samples across 91 studies and 81 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:54 O:3
• Conservation: PhyloP100: 5.57
• Publications: 1 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 ACGS-UK Somatic Oncogenicity v2025

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 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		ClinVar oncogenic/SCI T1 (multiple submitters, ★★) — Strong (O1); ClinVar oncogenic/SCI T1 (single/no review, ★0–1) — Moderate (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (4.0 pts): ClinVar (somatic oncogenic/LO (★★)), ClinVar germline P/LP in TSG (★★)
	O2Null variant in tumour suppressor gene		Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 876 citations, oncogene: 281 citations, driver: 265 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 801.
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000000 — very rare (O3 supporting [+1])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=540 | studies=91 | cancer types=81 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 1912, same AA change = 239; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 0 pathogenic, 0 benign; Variant does not impact splicing — splice-hotspot path not applicable

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>T p.Arg130*	stop_gained	Exon 5 of 9	Prot: NP_000305.3
	PTEN NM_001304718.2		c.-363C>T	5_prime_UTR_premature_start_codon_gain	Exon 4 of 9	Prot: NP_001291647.1
	PTEN NM_001304717.5		c.907C>T p.Arg303*	stop_gained	Exon 6 of 10	Prot: NP_001291646.4

PTEN NM_000314.8

MANE Select

HGVSc / HGVSpc.388C>Tp.Arg130*

Exon rankExon 5 of 9

stop_gained

Prot: NP_000305.3

PTEN NM_001304718.2

HGVSc / HGVSpc.-363C>T

Exon rankExon 4 of 9

5_prime_UTR_premature_start_codon_gain

Prot: NP_001291647.1

PTEN NM_001304717.5

HGVSc / HGVSpc.907C>Tp.Arg303*

Exon rankExon 6 of 10

stop_gained

Prot: NP_001291646.4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PTEN ENST00000371953.8	TSL:1MANE Select	c.388C>T p.Arg130*	stop_gained	Exon 5 of 9	Prot: ENSP00000361021.3 UniProt:
	PTEN ENST00000693560.1		c.907C>T p.Arg303*	stop_gained	Exon 6 of 10	Prot: ENSP00000509861.1 UniProt:
	PTEN ENST00000700029.2		c.388C>T p.Arg130*	stop_gained	Exon 5 of 10	Prot: ENSP00000514759.2 UniProt:

PTEN ENST00000371953.8

TSL:1MANE Select

HGVSc / HGVSpc.388C>Tp.Arg130*

Exon rankExon 5 of 9

stop_gained

Prot: ENSP00000361021.3UniProt: P60484-1

PTEN ENST00000693560.1

HGVSc / HGVSpc.907C>Tp.Arg303*

Exon rankExon 6 of 10

stop_gained

Prot: ENSP00000509861.1UniProt: P60484-2A0A8I5KSF9

PTEN ENST00000700029.2

HGVSc / HGVSpc.388C>Tp.Arg130*

Exon rankExon 5 of 10

stop_gained

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251384	Cov:
GnomAD4 exome	AF: 0.00000274	AC:4	Hom:0	AN:1461670	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000460	AC:1	Hom:0	AN:217316	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:121410	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41956	0.0000299	2	66886
SCHEMA(Schizophrenia)	0.00	0	67854	0.00000750	1	133312

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Cowden syndrome 1 (16)
10	-	-	not provided (10)
8	-	-	PTEN hamartoma tumor syndrome (8)
4	-	-	Hereditary cancer-predisposing syndrome (4)
4	-	-	Macrocephaly-autism syndrome (4)
3	-	-	PTEN-related disorder (3)
2	-	-	Glioma susceptibility 2 (2)
1	-	-	Abnormal cardiovascular system morphology (1)
1	-	-	Cowden syndrome (1)
1	-	-	Gastric cancer (1)
1	-	-	Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C2931456:Familial prostate cancer;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)
1	-	-	Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 (1)
1	-	-	Ovarian neoplasm (1)
1	-	-	Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 (1)
1	-	-	Rhabdomyosarcoma (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	42
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.95	D
GPN-Star LLR	N/A	-9.2
GPN-Star score	N/A	9.0
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	5.6

Showing 12 of 12 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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121909224;

hg19: chr10-89692904;

COSMIC: COSV64288463;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar