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PTENc.389_405delinsTAACTGGTGTAATGATGUncertain significance
Print report
Variant interpretation report

PTEN c.389_405delinsTAACTGGTGTAATGATG, p.(Arg130_Ile135delinsLeuThrGlyValMetMet)

NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG NP_000305.3:p.(Arg130_Ile135delinsLeuThrGlyValMetMet) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PTEN

No gene-level summary was recorded for this case.

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. 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate

This variant alters residues 130-135 of NP_000305.3. Residue 130 (Arg130) is the terminal residue of the P-loop/phosphatase core catalytic motif defined by the PTEN VCEP as residues 123-130. The variant replaces Arg130 with Leu, directly disrupting a critical catalytic domain.

PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).

PM4Moderate
PM4 · moderate

NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that alters residues 130-135, including residue Arg130 which lies within the P-loop catalytic motif (residues 123-130). Per PTEN VCEP specification, PM4 applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif specified under PM1.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PM2 supporting, PM4 moderate; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

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

SpliceAI score
0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion in exon 5 of PTEN, resulting in substitution of six residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet). Residue Arg130 is the terminal residue of the P-loop/phosphatase core catalytic motif (NP_000305.3 residues 123-130), a critical functional domain defined by the ClinGen PTEN Expert Panel.

The variant is absent from gnomAD v2.1 and v4.1 population databases, satisfying PM2 at supporting strength per PTEN VCEP specifications.

The variant alters the P-loop catalytic motif, satisfying PM1 at moderate strength per PTEN VCEP (catalytic motifs defined as residues 90-94, 123-130, 166-168). As an in-frame deletion-insertion impacting a catalytic motif residue, PM4 also applies at moderate strength per PTEN VCEP specification.

No variant-specific functional, segregation, de novo, or case-level evidence is available. Four publications provided in the literature packet (PMID:10866302, PMID:32350270, PMID:32366478, PMID:9467011) do not mention this variant. The Mighell et al. 2018 saturation mutagenesis assay (mmc2.xlsx) covers missense variants only and does not include in-frame indels.

Per PTEN VCEP combination rules, two moderate criteria (PM1, PM4) and one supporting criterion (PM2_Supporting) are insufficient to reach Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 3

PM1 ModerateThis variant alters residues 130-135 of NP_000305.3. Residue 130 (Arg130) is the terminal residue of the P-loop/phosphatase core catalytic motif defined by the PTEN VCEP as residues 123-130. The variant replaces Arg130 with Leu, directly disrupting a critical catalytic domain. Details ▾Hide ▴
Evidence considered
  • Variant alters residue 130 within the P-loop catalytic motif (residues 123-130 per PTEN VCEP PM1 specification). Cancer Hotspots confirms this region is a statistically significant mutational hotspot.
Sources
cspec ↗
PM2 SupportingThe variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles). Absent from gnomAD v4.1 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
PM4 ModerateNM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that alters residues 130-135, including residue Arg130 which lies within the P-loop catalytic motif (residues 123-130). Per PTEN VCEP specification, PM4 applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif specified under PM1. Details ▾Hide ▴
Evidence considered
  • In-frame deletion-insertion of 6 residues (p.Arg130_Ile135delinsLeuThrGlyValMetMet) impacting the catalytic P-loop motif at residue 130.
Sources
cspec ↗

Not met · 15 · evaluated, threshold not reached

PVS1 PTEN VCEP PVS1 decision tree applies to nonsense, frameshift, and canonical splice site variants. NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG is an in-frame deletion-insertion that does not introduce a premature stop codon or disrupt the reading frame; it does not fall within any PVS1 decision tree branch. Details ▾Hide ▴
Evidence considered
  • In-frame indel with no frameshift or nonsense change
  • PVS1 decision tree not applicable to this variant type.
Sources
vcep_pvs1_decisiontree_ptencspec ↗
PS1 No previously established pathogenic variant with the same amino acid change (p.Arg130_Ile135delinsLeuThrGlyValMetMet) has been identified. This is a novel 6-residue in-frame substitution not matching any known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no known pathogenic variant shares this amino acid change.
Sources
clinvar ↗cspec ↗
PS2 No de novo observation has been reported for this variant. No proband or family history data is available in the case materials. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No proband or family data provided for this case.
PS3 No variant-specific functional data is available. The PTEN VCEP PS3_Moderate pathway via Mighell et al. 2018 (PMID:29706350) phosphatase activity assay applies to missense variants only and does not cover in-frame indels. The four papers provided in the literature packet (PMID:10866302, PMID:32350270, PMID:32366478, PMID:9467011) do not mention this variant. Details ▾Hide ▴
Evidence considered
  • Mighell et al. saturation mutagenesis (mmc2.xlsx) covers missense variants only
  • this is an in-frame indel. Four functional papers reviewed — none contain this variant.
Still missing
  • No functional assay data available for in-frame indel variants of this type in PTEN.
Sources
cspec ↗vcep_mmc2
PS4 No proband or case-level data is available to calculate a specificity score or assess prevalence in affected individuals. PTEN VCEP PS4 requires proband counts with phenotype specificity scoring. Details ▾Hide ▴
Evidence considered
  • No proband or case-control data available.
Still missing
  • Proband data required for PS4 application.
Sources
cspec ↗
PM6 No de novo observation (assumed or confirmed) has been reported for this variant in any proband with PHTS or related phenotype. Details ▾Hide ▴
Evidence considered
  • No de novo data available.
Still missing
  • No proband data provided.
PP1 No co-segregation data is available. PTEN VCEP requires at least 3-4 meioses for PP1 at supporting strength. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Family segregation data required.
PP3 PTEN VCEP PP3 applies to missense variants with REVEL score >0.7 or splicing variants with concordant in silico predictions. REVEL does not compute scores for in-frame indels. SpliceAI predicts no significant splice impact (max delta score 0.03). No computational evidence supports a deleterious effect for this variant type. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.03 (no significant splice impact). REVEL not applicable to indels.
Sources
spliceai ↗cspec ↗
BA1 The variant is absent from gnomAD. PTEN VCEP BA1 threshold of filtering allele frequency >0.00056 (0.056%) is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 The variant is absent from gnomAD. PTEN VCEP BS1 threshold of filtering allele frequency ≥0.000043 (0.0043%) is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS2 No observation of this variant in the homozygous state in a healthy or PHTS-unaffected individual has been reported. Details ▾Hide ▴
Evidence considered
  • No homozygous observations in gnomAD or any other data source.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS3 No functional studies demonstrating no damaging effect on protein function are available for this variant. The PTEN VCEP BS3_Supporting pathway via Mighell et al. 2018 applies to missense variants with phosphatase activity >0 and does not cover in-frame indels. Details ▾Hide ▴
Evidence considered
  • No functional data demonstrating benign effect available. Mighell et al. missense assay not applicable to indels.
Still missing
  • No functional data available for this variant.
Sources
cspec ↗vcep_mmc2
BS4 No segregation data is available to demonstrate lack of segregation in affected family members. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • Family segregation data required.
BP2 No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/unknown phase with different pathogenic/likely pathogenic PTEN variants. Details ▾Hide ▴
Evidence considered
  • No phase data available.
Still missing
  • Phase data with other PTEN variants not available.
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. PTEN VCEP requires at least two such cases. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 is a missense-specific criterion requiring a different missense change at the same residue as a known pathogenic missense variant. This variant is a 6-residue in-frame deletion-insertion, not a single-residue missense substitution. PM5 candidate analysis confirmed not applicable. Details ▾Hide ▴
Evidence considered
  • Variant class is in-frame indel
  • not missense. PM5 candidate search returned no applicable comparators.
Sources
pm5_candidatescspec ↗
PP2 N/APTEN VCEP PP2 applies specifically to missense variants in a gene with a low rate of benign missense variation. This variant is an in-frame deletion-insertion, not a single-residue missense change. Details ▾Hide ▴
Evidence considered
  • Variant is in-frame indel
  • not missense
  • PP2 criterion not applicable.
Sources
cspec ↗
PP4 VCEPPTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into PS4 Use 2 within this framework. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPPTEN VCEP specifies PP5 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPPTEN VCEP specifies BP1 as Not Applicable; this rule is not applicable to PTEN as both truncating and missense variants are known mechanisms of disease. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPPTEN VCEP specifies BP3 as Not Applicable; this rule is not applicable to PTEN. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/APTEN VCEP BP4 applies to synonymous or intronic variants where in silico models predict no splicing impact, and to missense variants with REVEL score <0.5. This variant is an in-frame coding deletion-insertion; BP4 is not applicable to this variant type. Details ▾Hide ▴
Evidence considered
  • Variant type (in-frame indel) not covered by VCEP BP4 specification.
Sources
cspec ↗
BP6 VCEPPTEN VCEP specifies BP6 as Not Applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a coding in-frame deletion-insertion, not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is coding in-frame indel
  • not synonymous/intronic.
Sources
cspec ↗
PS5 N/APS5 is not a recognized ACMG/AMP criterion. Not included in the PTEN VCEP specifications. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG
Protein (HGVS p.)
NP_000305.3:p.(Arg130_Ile135delinsLeuThrGlyValMetMet)
GRCh38
chr10:87933148 GAACTGGTGTAATGATA>TAACTGGTGTAATGATG
GRCh37
chr10:89692905 GAACTGGTGTAATGATA>TAACTGGTGTAATGATG

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…
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 -153 bp
0.030
SpliceAI acceptor gainat +53 bp
0.010
SpliceAI donor lossat +103 bp
0.000
SpliceAI donor gainat -19 bp
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 PTEN VCEP PP3 applies to missense variants with REVEL score >0.7 or splicing variants with concordant in silico predictions. REVEL does not compute scores for in-frame indels. SpliceAI predicts no significant splice impact (max delta score 0.03). No computational evidence supports a deleterious effect for this variant type. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.03 (no significant splice impact). REVEL not applicable to indels.
Sources
spliceai ↗cspec ↗
BP4 N/APTEN VCEP BP4 applies to synonymous or intronic variants where in silico models predict no splicing impact, and to missense variants with REVEL score <0.5. This variant is an in-frame coding deletion-insertion; BP4 is not applicable to this variant type. Details ▾Hide ▴
Evidence considered
  • Variant type (in-frame indel) not covered by VCEP BP4 specification.
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splice impact. This variant is a coding in-frame deletion-insertion, not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is coding in-frame indel
  • not synonymous/intronic.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.
    Han et al. (2000) evaluated the in vitro phosphoinositide phosphatase activity of select PTEN missense mutations identified in human cancers and Cowden disease. NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG was not among the variants tested.
    Does not name this variant
    PMID 10866302 ↗
  • Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction.
    Post et al. (2020) performed multi-model functional characterization of 106 PTEN missense and nonsense variants associated with ASD, somatic cancer, and PHTS, assessing lipid phosphatase activity, protein stability, and subcellular localization. The in-frame indel NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG was not among the variants studied.
    Does not name this variant
    PMID 32350270 ↗
  • A Premalignant Cell-Based Model for Functionalization and Classification of PTEN Variants.
    Chao et al. (2020) developed a premalignant cell-based model for functional classification of PTEN variants. NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG was not among the variants evaluated.
    Does not name this variant
    PMID 32366478 ↗
  • Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
    Marsh et al. (1998) reported the PTEN mutation spectrum and genotype-phenotype correlations in Cowden disease and Bannayan-Zonana syndrome, identifying predominantly nonsense, frameshift, and missense germline mutations. NM_000314.8:c.389_405delinsTAACTGGTGTAATGATG was not described in this cohort.
    Does not name this variant
    PMID 9467011 ↗

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 0.030 Open source ↗
ClinVar Captured ClinVar source record 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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

Somatic

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.