NM_000314.8:c.388_390delCGAinsAGG

Variant names:

• chr10-87933147-CGA-AGG
• NM_000314.8:c.388_390delCGAinsAGG
• PTEN p.131

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_StrongB4_Supporting

The NM_000314.8(PTEN):c.388_390delCGAinsAGG (p.131) variant causes a synonymous change. 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). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.52). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 9.53
• Publications: 0 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 5 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 outside canonical splice sites (B4 supporting); Synonymous variant — splicing impact not confirmed absent; B4 supporting [-1]

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.388_390delCGAinsAGG p.131	synonymous	N/A	Prot: NP_000305.3
	PTEN NM_001304717.5		c.907_909delCGAinsAGG p.304	synonymous	N/A	Prot: NP_001291646.4
	PTEN NM_001304718.2		c.-363_-361delCGAinsAGG	5_prime_UTR	Exon 4 of 9	Prot: NP_001291647.1

PTEN NM_000314.8

MANE Select

HGVSc / HGVSpc.388_390delCGAinsAGGp.131

Exon rankN/A

synonymous

Prot: NP_000305.3

PTEN NM_001304717.5

HGVSc / HGVSpc.907_909delCGAinsAGGp.304

Exon rankN/A

synonymous

Prot: NP_001291646.4

PTEN NM_001304718.2

HGVSc / HGVSpc.-363_-361delCGAinsAGG

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.388_390delCGAinsAGG p.131	synonymous	N/A	Prot: ENSP00000361021.3 UniProt:
	PTEN ENST00000693560.1		c.907_909delCGAinsAGG p.304	synonymous	N/A	Prot: ENSP00000509861.1 UniProt:
	PTEN ENST00000700029.2		c.388_390delCGAinsAGG p.131	synonymous	N/A	Prot: ENSP00000514759.2 UniProt:

PTEN ENST00000371953.8

TSL:1MANE Select

HGVSc / HGVSpc.388_390delCGAinsAGGp.131

Exon rankN/A

synonymous

Prot: ENSP00000361021.3UniProt: P60484-1

PTEN ENST00000693560.1

HGVSc / HGVSpc.907_909delCGAinsAGGp.304

Exon rankN/A

synonymous

Prot: ENSP00000509861.1UniProt: P60484-2A0A8I5KSF9

PTEN ENST00000700029.2

HGVSc / HGVSpc.388_390delCGAinsAGGp.131

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.5

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr10-89692904;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar