chr10-87933149-A-T

Variant names:

• chr10-87933149-A-T
• rs963598711
• NM_000314.8:c.390A>T
• PTEN p.Arg130Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_StrongB4_Strong

The NM_000314.8(PTEN):c.390A>T (p.Arg130Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★). 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.09
• Publications: 7 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	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
	B4Synonymous/intronic, no splicing impact		Synonymous/intronic variant with confirmed no splicing impact (B4 strong); Synonymous variant — splicing algorithms confirm no impact on splicing (B4 strong [-4])

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.390A>T p.Arg130Arg	synonymous	Exon 5 of 9	Prot: NP_000305.3
	PTEN NM_001304717.5		c.909A>T p.Arg303Arg	synonymous	Exon 6 of 10	Prot: NP_001291646.4
	PTEN NM_001304718.2		c.-361A>T	5_prime_UTR	Exon 4 of 9	Prot: NP_001291647.1

PTEN NM_000314.8

MANE Select

HGVSc / HGVSpc.390A>Tp.Arg130Arg

Exon rankExon 5 of 9

synonymous

Prot: NP_000305.3

PTEN NM_001304717.5

HGVSc / HGVSpc.909A>Tp.Arg303Arg

Exon rankExon 6 of 10

synonymous

Prot: NP_001291646.4

PTEN NM_001304718.2

HGVSc / HGVSpc.-361A>T

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.390A>T p.Arg130Arg	synonymous	Exon 5 of 9	Prot: ENSP00000361021.3 UniProt:
	PTEN ENST00000693560.1		c.909A>T p.Arg303Arg	synonymous	Exon 6 of 10	Prot: ENSP00000509861.1 UniProt:
	PTEN ENST00000700029.2		c.390A>T p.Arg130Arg	synonymous	Exon 5 of 10	Prot: ENSP00000514759.2 UniProt:

PTEN ENST00000371953.8

TSL:1MANE Select

HGVSc / HGVSpc.390A>Tp.Arg130Arg

Exon rankExon 5 of 9

synonymous

Prot: ENSP00000361021.3UniProt: P60484-1

PTEN ENST00000693560.1

HGVSc / HGVSpc.909A>Tp.Arg303Arg

Exon rankExon 6 of 10

synonymous

Prot: ENSP00000509861.1UniProt: P60484-2A0A8I5KSF9

PTEN ENST00000700029.2

HGVSc / HGVSpc.390A>Tp.Arg130Arg

Exon rankExon 5 of 10

synonymous

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 4 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
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:17394	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	PTEN hamartoma tumor syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.63
GPN-Star LLR	N/A	-5.7
GPN-Star score	N/A	5.7
PhyloP100	Benign	2.1

Showing 7 of 7 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.

4 no calibration

4 assays found for this variant.

No calibration: 4 assays (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

PTEN VAMP-seq Fill-in

• Gene: PTEN
• Score: 1.12 · p.Arg130Arg (assay numbering)

No calibration data

This score is at approximately the 81th 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: 0.903 · p.Arg130Arg (assay numbering)

No calibration data

This score is at approximately the 68th 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 Variant Imaging in Neurons

• Gene: PTEN
• Assay type: Other
• Model system: Induced pluripotent stem cells from human male
• Score: 0.143 · p.Arg130Arg (assay numbering)

No calibration data

This score is at approximately the 5th 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 VIS-seq in hiPSCs

PTEN Variant Imaging in hiPSCs

• Gene: PTEN
• Assay type: Other
• Model system: Induced pluripotent stem cells from human male
• Score: 0.143 · p.Arg130Arg (assay numbering)

No calibration data

This score is at approximately the 5th 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: rs963598711;

hg19: chr10-89692906;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar