10-87933147-CGA-GGT

Variant names:

• chr10-87933147-CGA-GGT
• NM_000314.8:c.388_390delCGAinsGGT
• 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 15 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5PP2

The NM_000314.8(PTEN):c.388_390delCGAinsGGT (p.Arg130Gly) variant causes a missense change. 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. 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) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. 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: 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 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 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	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×).

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_390delCGAinsGGT p.Arg130Gly	missense	N/A	Prot: NP_000305.3
	PTEN NM_001304717.5		c.907_909delCGAinsGGT p.Arg303Gly	missense	N/A	Prot: NP_001291646.4
	PTEN NM_001304718.2		c.-363_-361delCGAinsGGT	5_prime_UTR	Exon 4 of 9	Prot: NP_001291647.1

PTEN NM_000314.8

MANE Select

HGVSc / HGVSpc.388_390delCGAinsGGTp.Arg130Gly

Exon rankN/A

missense

Prot: NP_000305.3

PTEN NM_001304717.5

HGVSc / HGVSpc.907_909delCGAinsGGTp.Arg303Gly

Exon rankN/A

missense

Prot: NP_001291646.4

PTEN NM_001304718.2

HGVSc / HGVSpc.-363_-361delCGAinsGGT

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_390delCGAinsGGT p.Arg130Gly	missense	N/A	Prot: ENSP00000361021.3 UniProt:
	PTEN ENST00000693560.1		c.907_909delCGAinsGGT p.Arg303Gly	missense	N/A	Prot: ENSP00000509861.1 UniProt:
	PTEN ENST00000700029.2		c.388_390delCGAinsGGT p.Arg130Gly	missense	N/A	Prot: ENSP00000514759.2 UniProt:

PTEN ENST00000371953.8

TSL:1MANE Select

HGVSc / HGVSpc.388_390delCGAinsGGTp.Arg130Gly

Exon rankN/A

missense

Prot: ENSP00000361021.3UniProt: P60484-1

PTEN ENST00000693560.1

HGVSc / HGVSpc.907_909delCGAinsGGTp.Arg303Gly

Exon rankN/A

missense

Prot: ENSP00000509861.1UniProt: P60484-2A0A8I5KSF9

PTEN ENST00000700029.2

HGVSc / HGVSpc.388_390delCGAinsGGTp.Arg130Gly

Exon rankN/A

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 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.

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

hg19: chr10-89692904;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar