PTENc.388C>GLikely pathogenic

Print report

Variant interpretation report

PTEN c.388C>G, p.(Arg130Gly)

NM_000314.8:c.388C>G NP_000305.3:p.(Arg130Gly) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 moderate (pathogenic) · 4 supporting (pathogenic)
Expert rules: ClinGen PTEN VCEP v3.2.0
Other laboratories (ClinVar): 4 Pathogenic · 1 Likely pathogenic
Pipeline record: 1 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PS3 (moderate): PTEN phosphatase activity assay (Mighell et al. 2018, saturation mutagenesis) yields a cumulative fitness score (Cum_score) of -2.14 for R130G (High_conf=True), meeting the VCEP threshold of ≤ -1.11 for PS3_Moderate. Additionally, R130G was shown to produce fully inactive PTEN protein in a yeast-based in vivo PIP3 phosphatase assay (PMID:21828076) and abrogated tumor suppressive activity including colony formation and growth inhibition in glioma cells (PMID:11948419).
PM1 (moderate): Arg130 is located within the PTEN catalytic P-loop (residues 123–130, NP_000305.3), which is a critical and well-established functional domain defined by the VCEP as a mutational hotspot and catalytic motif. The P-loop contains the essential catalytic Cys124 and Arg130 residues at the active site. Residue 130 is a statistically significant hotspot.
PM2 (supporting): NM_000314.8:c.388C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Allele frequency is <0.00001 (0.001%) across all populations, meeting the PTEN VCEP PM2_Supporting threshold.
PM5 (moderate): R130G is a missense change at Arg130, where other missense changes (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar and associated with Cowden syndrome/PHTS in the literature. The interrogated variant R130G has a BLOSUM62 score of -2 (Arg→Gly), which is less than or equal to known pathogenic variants at this residue (R130Q: +1, R130L: -2, R130P: -2), satisfying the VCEP PM5 BLOSUM62 requirement.
PP2 (supporting): PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, Cowden syndrome). The variant is a missense change, satisfying the VCEP PP2 rule.
PP3 (supporting): REVEL score of 0.962 exceeds the VCEP threshold of >0.7 for PP3 supporting evidence. Multiple lines of computational evidence support a deleterious effect: REVEL 0.962 (highly deleterious), BayesDel 0.581 (deleterious). SpliceAI max delta 0.02 indicates no splicing impact, consistent with a missense mechanism of pathogenicity rather than splicing.
PP5 (supporting): Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen PTEN VCEP v3.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 7 Benign evidence criteria: 0

Pathogenic criteria applied · 7

PS3Moderate

PS3 · moderate

PTEN phosphatase activity assay (Mighell et al. 2018, saturation mutagenesis) yields a cumulative fitness score (Cum_score) of -2.14 for R130G (High_conf=True), meeting the VCEP threshold of ≤ -1.11 for PS3_Moderate. Additionally, R130G was shown to produce fully inactive PTEN protein in a yeast-based in vivo PIP3 phosphatase assay (PMID:21828076) and abrogated tumor suppressive activity including colony formation and growth inhibition in glioma cells (PMID:11948419).

PM1Moderate

PM1 · moderate

Arg130 is located within the PTEN catalytic P-loop (residues 123–130, NP_000305.3), which is a critical and well-established functional domain defined by the VCEP as a mutational hotspot and catalytic motif. The P-loop contains the essential catalytic Cys124 and Arg130 residues at the active site. Residue 130 is a statistically significant hotspot.

PM2Supporting

PM2 · supporting

NM_000314.8:c.388C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Allele frequency is <0.00001 (0.001%) across all populations, meeting the PTEN VCEP PM2_Supporting threshold.

PM5Moderate

PM5 · moderate

R130G is a missense change at Arg130, where other missense changes (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar and associated with Cowden syndrome/PHTS in the literature. The interrogated variant R130G has a BLOSUM62 score of -2 (Arg→Gly), which is less than or equal to known pathogenic variants at this residue (R130Q: +1, R130L: -2, R130P: -2), satisfying the VCEP PM5 BLOSUM62 requirement.

PP2Supporting

PP2 · supporting

PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, Cowden syndrome). The variant is a missense change, satisfying the VCEP PP2 rule.

PP3Supporting

PP3 · supporting

REVEL score of 0.962 exceeds the VCEP threshold of >0.7 for PP3 supporting evidence. Multiple lines of computational evidence support a deleterious effect: REVEL 0.962 (highly deleterious), BayesDel 0.581 (deleterious). SpliceAI max delta 0.02 indicates no splicing impact, consistent with a missense mechanism of pathogenicity rather than splicing.

PP5Supporting

PP5 · supporting

Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule13 (Pathogenic.Moderate >=3) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

5 reported laboratory submissions

4 Pathogenic · 1 Likely pathogenic.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

259 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64288384, n = 259 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.

27 criteria with recorded statuses: 7 met · 6 not met · 7 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000314.8:c.388C>G (p.Arg130Gly) in PTEN is classified as Likely Pathogenic per the ClinGen PTEN Expert Panel Specifications Version 3.2.0, based on three moderate and three supporting criteria.

The variant is located in the PTEN catalytic P-loop (Arg130, residues 123–130), a critical functional domain defined by the VCEP as a mutational hotspot and catalytic motif (PM1).

PTEN phosphatase activity assay via saturation mutagenesis (Mighell et al. 2018) yields Cum_score = -2.14 (High_conf = True), meeting the VCEP PS3_Moderate threshold of ≤ -1.11. Functional studies demonstrate that R130G produces fully inactive PTEN protein with complete loss of PIP3 phosphatase activity in yeast (PMID:21828076) and abrogated tumor suppressive function in glioma cells (PMID:11948419).

Other missense changes at Arg130 (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar in association with Cowden syndrome/PHTS, and the BLOSUM62 score of R130G (-2) is less than or equal to these comparators, satisfying PM5.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold of <0.001% allele frequency.

PP2 applies as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism. PP3 applies with a REVEL score of 0.962 (>0.7 threshold).

The variant has been reported in ClinVar as Pathogenic by the Clingen PTEN Variant Curation Expert Panel (expert panel review) and as Pathogenic by four clinical laboratories. It is also reported in COSMIC (259 somatic observations) and classified as Oncogenic (loss-of-function) by OncoKB.

Applying the PTEN VCEP classification combining rules: ≥3 moderate criteria (PS3_Moderate, PM1, PM5) satisfies Rule13 for Likely Pathogenic. The ClinVar expert panel classification of Pathogenic suggests additional proband-level evidence (PS4) may be available to elevate this to Pathogenic.

Met · 7

PS3 ModeratePTEN phosphatase activity assay (Mighell et al. 2018, saturation mutagenesis) yields a cumulative fitness score (Cum_score) of -2.14 for R130G (High_conf=True), meeting the VCEP threshold of ≤ -1.11 for PS3_Moderate. Additionally, R130G was shown to produce fully inactive PTEN protein in a yeast-based in vivo PIP3 phosphatase assay (PMID:21828076) and abrogated tumor suppressive activity including colony formation and growth inhibition in glioma cells (PMID:11948419). Details ▾Hide ▴

Evidence considered

Mighell et al. 2018 (mmc2.xlsx Table S2): R130G Cum_score = -2.13842062 (≤ -1.11 threshold)
High_conf = True
PMID:21828076: R130G resulted in fully inactive PTEN in yeast PIP3 phosphatase assay
listed among tumor-associated P-loop mutations with complete loss of function
PMID:11948419: R130G abrogated PTEN lipid phosphatase activity and tumor suppression in U251 glioma cells
failed to decrease colony formation
growth rate
and saturation density in vitro
and failed to block tumor formation in vivo

Sources

vcep_mmc2PMID:21828076 ↗PMID:11948419 ↗

PM1 ModerateArg130 is located within the PTEN catalytic P-loop (residues 123–130, NP_000305.3), which is a critical and well-established functional domain defined by the VCEP as a mutational hotspot and catalytic motif. The P-loop contains the essential catalytic Cys124 and Arg130 residues at the active site. Residue 130 is a statistically significant hotspot. Details ▾Hide ▴

Evidence considered

PTEN VCEP PM1 rule: residues in catalytic motifs 90–94
123–130
166–168 (NP_000305.3) qualify for PM1
Arg130 is within the 123–130 P-loop catalytic motif
Statistically significant hotspot at this residue

Sources

cspec ↗

PM2 SupportingNM_000314.8:c.388C>G is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes + genomes), and gnomAD-Canada v1.0. Allele frequency is <0.00001 (0.001%) across all populations, meeting the PTEN VCEP PM2_Supporting threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent
gnomAD-Canada v1.0: absent (AC=0
AN=0)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM5 ModerateR130G is a missense change at Arg130, where other missense changes (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar and associated with Cowden syndrome/PHTS in the literature. The interrogated variant R130G has a BLOSUM62 score of -2 (Arg→Gly), which is less than or equal to known pathogenic variants at this residue (R130Q: +1, R130L: -2, R130P: -2), satisfying the VCEP PM5 BLOSUM62 requirement. Details ▾Hide ▴

Evidence considered

R130Q is ClinVar Pathogenic (Cowden syndrome/PHTS)
BLOSUM62 = +1
R130L is ClinVar Pathogenic (Cowden syndrome/PHTS)
BLOSUM62 = -2
R130P is ClinVar Pathogenic
R130G BLOSUM62 = -2 ≤ R130Q (+1) and ≤ R130L (-2) and ≤ R130P (-2)

Sources

clinvar ↗vcep_mmc2

PP2 SupportingPTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, Cowden syndrome). The variant is a missense change, satisfying the VCEP PP2 rule. Details ▾Hide ▴

Evidence considered

PTEN VCEP PP2 rule: missense variant in a gene with low rate of benign missense variation and missense as common disease mechanism
gnomAD shows very few PTEN missense variants
consistent with low benign missense variation

Sources

cspec ↗

PP3 SupportingREVEL score of 0.962 exceeds the VCEP threshold of >0.7 for PP3 supporting evidence. Multiple lines of computational evidence support a deleterious effect: REVEL 0.962 (highly deleterious), BayesDel 0.581 (deleterious). SpliceAI max delta 0.02 indicates no splicing impact, consistent with a missense mechanism of pathogenicity rather than splicing. Details ▾Hide ▴

Evidence considered

REVEL score: 0.962 (>0.7 threshold per PTEN VCEP)
BayesDel score: 0.581379 (deleterious)
SpliceAI max delta: 0.02 (no splicing impact
consistent with missense pathogenicity mechanism)

Sources

revelbayesdelspliceai ↗

PP5 SupportingExpert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 6 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at NM_000314.8:c.388 that produces the same p.Arg130Gly amino acid substitution. The codon CGA can only yield Gly via a C>G transversion at the first position; no alternative nucleotide change creates R130G at this residue. Details ▾Hide ▴

Evidence considered

Only one nucleotide change (c.388C>G) produces R130G from the wild-type CGA codon
no alternate pathogenic nucleotide variant generating the same amino acid change was identified.

BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the PTEN VCEP BA1 threshold of allele frequency >0.00056 (0.056%). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 Variant is absent from all gnomAD populations. Does not meet the PTEN VCEP BS1 threshold (AF ≥0.0000043 for supporting or ≥0.000043 for strong). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: absent
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 No homozygous observations in gnomAD or other population databases. The variant is entirely absent from population cohorts, providing no evidence of homozygous or healthy adult occurrence. Details ▾Hide ▴

Evidence considered

Variant absent from all gnomAD populations
no homozygous observations.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 PTEN phosphatase activity assay (Mighell et al. 2018) shows Cum_score = -2.14 for R130G, which is ≤0 and indicates damaging effect. BS3_Supporting requires phosphatase activity >0. The variant does not meet BS3 criteria. BS3_Strong applies only to splicing assays (not relevant for this missense variant). Details ▾Hide ▴

Evidence considered

R130G Cum_score = -2.14 (≤0)
damaging
not benign. Does not meet BS3_Supporting threshold of >0.

Sources

vcep_mmc2

BP4 REVEL score of 0.962 exceeds the VCEP BP4 threshold of <0.5 for benign computational evidence. Multiple in silico predictions support a deleterious effect, not a benign one. Details ▾Hide ▴

Evidence considered

REVEL: 0.962 (≥0.5
does not meet BP4 threshold of <0.5)
BayesDel: 0.581 (deleterious)

Sources

revelbayesdel

Not assessed · 7 · no assessment recorded

PS2 No de novo observation data (maternity and paternity confirmed) available in the case evidence for NM_000314.8:c.388C>G. ClinVar submissions and reviewed literature do not report a confirmed de novo occurrence. Details ▾Hide ▴

Still missing

No de novo reports identified
proband-level data would be needed to assess PS2.

PS4 Proband specificity scores and case-control data required for PS4 strength determination per the PTEN VCEP are not available in the evidence provided. The variant is classified as Pathogenic in ClinVar (reviewed by expert panel, multiple clinical laboratory submissions), suggesting significant proband-level data exist, but the raw counts needed to calculate specificity scores were not located. Details ▾Hide ▴

Evidence considered

ClinVar: Pathogenic classification by Clingen PTEN VCEP (expert panel)
with 4 clinical laboratories reporting Pathogenic and 1 reporting Likely pathogenic.

Still missing

Proband counts and phenotype specificity scores not available for PS4 strength calculation per VCEP specificity score thresholds (≥16 = Very Strong
4–15.5 = Strong
2–3.5 = Moderate
1–1.5 = Supporting).

Sources

clinvar ↗

PM6 No de novo occurrence data (assumed or confirmed) available for this variant. ClinVar submissions and reviewed literature do not report de novo observations. Details ▾Hide ▴

Still missing

No de novo reports identified.

PP1 No co-segregation data available in the evidence provided. Family-level meiotic data would be needed to assess co-segregation with disease. Details ▾Hide ▴

Still missing

No co-segregation or family data available.

BS4 No segregation data available to assess lack of segregation in affected family members. Details ▾Hide ▴

Still missing

No family segregation data available.

BP2 No data on observations in trans or cis with pathogenic PTEN variants available. Details ▾Hide ▴

Still missing

No data on co-occurrence with other PTEN pathogenic variants in cis or trans.

BP5 No evidence of an alternate molecular basis for disease in a proband carrying this variant. Individual case-level data would be required. Details ▾Hide ▴

Still missing

No data on cases with alternate molecular diagnoses.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant (c.388C>G, p.Arg130Gly). The PTEN VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical ±1,2 splice site disruptions, and single/multi-exon deletions). Missense variants are not eligible for PVS1 under this framework. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPPP4 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0. Phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴

Sources

cspec ↗

BP1 VCEPBP1 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0. Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPSkipped per instruction: in-frame indels not relevant to this substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is explicitly marked as Not Applicable by the ClinGen PTEN Expert Panel Specifications Version 3.2.0. Details ▾Hide ▴

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous (silent) or intronic variants for which splicing prediction algorithms predict no impact. NM_000314.8:c.388C>G is a missense variant producing p.Arg130Gly and does not qualify. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not defined in the ClinGen PTEN Expert Panel Specifications Version 3.2.0. The criterion is not part of the PTEN VCEP framework. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PTEN
Transcript: NM_000314.8
Coding (HGVS c.): NM_000314.8:c.388C>G
Protein (HGVS p.): NP_000305.3:p.(Arg130Gly)
GRCh38: chr10:87933147 C>G
GRCh37: chr10:89692904 C>G
ClinVar: 375958, 376509
COSMIC: COSV64288384

Gene diagram

Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.

PTENNM_000314.8

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in PTEN — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -152 bp

0.020

SpliceAI acceptor gainat +54 bp

0.000

SpliceAI donor lossat +104 bp

0.000

SpliceAI donor gainat -18 bp

0.000

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.000

Other predictors

REVEL: 0.962
BayesDel: 0.581

How the predictions were used

Evidence considered

REVEL score: 0.962 (>0.7 threshold per PTEN VCEP)
BayesDel score: 0.581379 (deleterious)
SpliceAI max delta: 0.02 (no splicing impact
consistent with missense pathogenicity mechanism)

Sources

revelbayesdelspliceai ↗

BP4 REVEL score of 0.962 exceeds the VCEP BP4 threshold of <0.5 for benign computational evidence. Multiple in silico predictions support a deleterious effect, not a benign one. Details ▾Hide ▴

Evidence considered

REVEL: 0.962 (≥0.5
does not meet BP4 threshold of <0.5)
BayesDel: 0.581 (deleterious)

Sources

revelbayesdel

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.962. BayesDel score = 0.581379.

6 paper records listed. 2 cited in the classification.

Cited in the classification

Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity.

Koul D et al. · 2002 Apr 4

R130G (p.Arg130Gly) mutation in the PTEN phosphatase domain was tested in U251 glioma cells. R130G abrogated PTEN lipid phosphatase activity toward PtdIns(3,4)P2 in vitro and eliminated tumor suppressive function, failing to suppress colony formation in soft agar, failing to decrease growth rate and saturation density in vitro, and failing to inhibit tumor formation in nude mice.
→ PS3 Names this variant
PMID 11948419 ↗
Source detail

Mutations at C124S and R130G abrogated the ability of MMAC/PTEN to decrease colony formation under anchorage-dependent conditions and to decrease growth rate and saturation density in vitro as well as to block tumor formation in vivo.

Location Results (Figure 1a schematic; Figure 2a,b colony formation; Figure 3 tumor formation in vivo; Figure 4 PtdIns phosphatase activity; Table 1 doubling time; Table 2 colony formation)

Context U251 human glioma cells stably expressing wild-type or mutant PTEN via retroviral transduction; in vitro PtdIns phosphatase assay using membrane micelles; in vivo tumor xenografts in nude mice
A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.

Rodríguez-Escudero I et al. · 2011 Nov 1

R130G (c.388C>G, p.Arg130Gly) was among tumor-associated PTEN P-loop mutations tested. R130G produced fully inactive PTEN protein, completely abrogating PIP3 phosphatase activity in the yeast in vivo assay. Listed as a PHTS-associated germline mutation with complete loss of function.
→ PS3 Names this variant
PMID 21828076 ↗
Source detail

G129V, G129R, R130G, T131A and T131I) gave rise to proteins that were fully inactive

Location Results, paragraph on tumor-related mutations (Fig. 4); Discussion of PHTS-associated mutations (Fig. 6A and Supplementary Table S1)

Context Yeast (S. cerevisiae) heterologous expression system with p110α-CAAX co-expression; PIP3 phosphatase activity measured by GFP-Akt1 plasma membrane relocalization and growth rescue

Other recorded publications

Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.

Han SY et al. · 2000

Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. The abstract discusses PTEN phosphatase activity and tumor-related mutations but does not specifically confirm evaluation of NM_000314.8:c.388C>G (p.Arg130Gly). Full text was not available for confirmation.
Does not name this variant
PMID 10866302 ↗
Functional evaluation of p53 and PTEN gene mutations in gliomas.

Kato H et al. · 2000

Screened p53 and PTEN mutations in 66 human brain tumors using yeast-based functional assay and cDNA-based direct sequencing. The abstract does not mention NM_000314.8:c.388C>G (p.Arg130Gly). Full text was not available for confirmation.
Does not name this variant
PMID 11051241 ↗
In vivo functional analysis of the counterbalance of hyperactive phosphatidylinositol 3-kinase p110 catalytic oncoproteins by the tumor suppressor PTEN.

Andrés-Pons A et al. · 2007

This study examined functional properties of PTEN mutations using a yeast-based in vivo system. R130Q was tested and mentioned, but NM_000314.8:c.388C>G (p.Arg130Gly) was not identified in this paper.
Does not name this variant
PMID 17942903 ↗
[MR angiography of the forearm--visualization of the internal dialysis shunt].

Nakatsuka H et al. · 1991

Phase contrast MR angiography of the forearm in healthy volunteers and patients with chronic renal failure. This is a radiology paper unrelated to PTEN and does not mention NM_000314.8:c.388C>G. Likely a ClinVar citation error (may have been intended as PMID:19457929).
Does not name this variant
PMID 1945792 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗

ClinVar 4 Pathogenic · 1 Likely pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 375958)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.962. BayesDel score = 0.581379.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64288384, n = 259 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.