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PTENc.993C>AUncertain significance
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Variant interpretation report

PTEN c.993C>A, p.(Asp331Glu)

NM_000314.8:c.993C>A NP_000305.3:p.(Asp331Glu) 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 v3.2.0. 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%).

PP2Supporting
PP2 · supporting

PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, meeting the VCEP PP2_Supporting criterion.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting; 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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 does not lie 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.

26 criteria with recorded statuses: 2 met · 10 not met · 8 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000314.8:c.993C>A (p.Asp331Glu) in PTEN has a cumulative fitness score of -0.106 in the Mighell et al. 2018 saturation mutagenesis assay, indicating near-wild-type phosphatase activity that does not meet PS3 or BS3 thresholds.

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

PP2_Supporting is applied as PTEN has a low rate of benign missense variation and missense variants are a well-established disease mechanism.

The variant does not reside in VCEP-defined catalytic motifs (residues 90-94, 123-130, 166-168) and is not in a statistically significant hotspot, so PM1 is not met.

REVEL score of 0.622 does not meet PP3 threshold (>0.7) or BP4 threshold (<0.5); computational evidence is indeterminate.

No pathogenic or likely pathogenic comparator variant at codon 331 was identified in ClinVar; PM5 is not met.

PVS1 is not applicable as this is a missense variant outside the scope of the PTEN PVS1 decision tree. PS2, PS4, PM6, PP1, BS4, BP2, and BP5 could not be assessed due to absence of clinical, de novo, segregation, or co-occurrence data.

With two supporting pathogenic criteria (PM2_Supporting, PP2_Supporting) and no moderate, strong, or very-strong criteria met, the variant does not reach Likely Pathogenic under the PTEN VCEP combination rules. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingVariant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the 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).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗
PP2 SupportingPTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, meeting the VCEP PP2_Supporting criterion. Details ▾Hide ▴
Evidence considered
  • PTEN has a low rate of benign missense variation
  • missense variants are a well-established disease mechanism in PTEN-related disorders.
Sources
cspec ↗

Not met · 10 · evaluated, threshold not reached

PS1 No prior pathogenic or likely pathogenic classification exists for the same amino acid change (p.Asp331Glu) at this residue. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no established pathogenic classification for D331E.
Sources
clinvar ↗
PS3 D331E cumulative fitness score (Cum_score) of -0.106 from the Mighell et al. 2018 (PMID: 29706350) massively parallel phosphatase activity assay does not meet PS3_Moderate threshold (Cum_score ≤ -1.11) and does not indicate phosphatase activity <50% of wild-type for PS3_Supporting. SpliceAI predicts no splicing impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 Table S2: D331E Cum_score = -0.106
  • High_conf = True. Thresholds not met.
  • SpliceAI max delta = 0.00
  • no splicing impact.
Sources
vcep_mmc2spliceai ↗
PM1 Residue 331 (p.Asp331) resides in the C2 domain, not within the VCEP-defined catalytic motifs at residues 90-94, 123-130, or 166-168 of NP_000305.3. Does not lie in a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
  • VCEP PM1 limits eligible residues to catalytic motifs 90-94
  • 123-130
  • 166-168. Residue 331 is in the C2 domain.
  • Not in a statistically significant hotspot.
Sources
cspec ↗
PM5 No pathogenic or likely pathogenic missense variant at codon 331 has been identified in ClinVar to serve as a comparator for the PM5 same-residue missense change rule. Details ▾Hide ▴
Evidence considered
  • No P/LP comparator missense variants at codon 331 identified in ClinVar or VCEP materials.
Sources
clinvar ↗pm5_candidates
PP3 REVEL score of 0.622 does not meet the VCEP PP3 threshold of >0.7. BayesDel score of -0.042 does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.622 (threshold >0.7 not met).
  • BayesDel score = -0.042 (does not support deleterious effect).
  • SpliceAI max delta = 0.00.
Sources
revelbayesdelspliceai ↗cspec ↗
BA1 Variant is absent from gnomAD and does not exceed the VCEP BA1 allele frequency threshold of >0.00056 (0.056%). Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
  • allele frequency = 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 Variant is absent from gnomAD and does not meet BS1 allele frequency thresholds (≥0.0000043 for BS1_Supporting; ≥0.000043 for BS1_Strong). Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
  • allele frequency = 0.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS2 No homozygous observations in healthy or PHTS-unaffected individuals identified. Details ▾Hide ▴
Evidence considered
  • No homozygous observations in gnomAD v2.1
  • v4.1
  • or gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018. D331E cumulative fitness score of -0.106 is not >0. BS3_Strong requires a splicing assay for intronic or synonymous variants, which is not applicable to this missense variant. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 Table S2: D331E Cum_score = -0.106
  • not meeting BS3_Supporting threshold (>0).
Sources
vcep_mmc2cspec ↗
BP4 REVEL score of 0.622 is not <0.5, failing the VCEP BP4 threshold for missense variants. Multiple computational lines do not consistently suggest no impact. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.622 (threshold <0.5 not met).
  • BayesDel score = -0.042 (near zero
  • indeterminate).
Sources
revelbayesdelspliceai ↗cspec ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports identified in literature or clinical databases.
PS4 No proband or case-control data available. The variant is absent from ClinVar with no clinical submissions. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no proband counts or phenotype data available.
Still missing
  • No proband or case-control data identified.
Sources
clinvar ↗
PM6 No de novo observation data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo reports identified in literature or clinical databases.
PP1 No co-segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data identified.
BS4 No segregation data available to assess lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No family segregation data identified.
BP2 No data available on co-occurrence in trans or cis with other pathogenic or likely pathogenic PTEN variants. Details ▾Hide ▴
Still missing
  • No co-occurrence data with other P/LP PTEN variants identified.
BP5 No data on an alternate molecular basis for disease in a case carrying this variant. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data identified.
PS5 PS5 is not defined by the ClinGen PTEN VCEP specification version 3.2.0. No VCEP rule framework exists for this criterion in the current gene-specific guideline. Details ▾Hide ▴
Evidence considered
  • PS5 absent from PTEN VCEP criteria specification.
Still missing
  • Criterion not defined in PTEN VCEP framework.
Sources
cspec ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.993C>A, p.Asp331Glu). The PTEN VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical GT-AG splice site, and CNV variants. Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a null variant covered by the PTEN PVS1 decision tree.
Sources
pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_decisiontree_pten
PP4 VCEPThe ClinGen PTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP designates PP4 as Not Applicable.
Sources
cspec ↗
PP5 VCEPThe ClinGen PTEN VCEP specifies PP5 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP designates PP5 as Not Applicable.
Sources
cspec ↗
BP1 VCEPThe ClinGen PTEN VCEP specifies BP1 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP designates BP1 as Not Applicable.
Sources
cspec ↗
BP6 VCEPThe ClinGen PTEN VCEP specifies BP6 as Not Applicable. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP designates BP6 as Not Applicable.
Sources
cspec ↗
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 applies only to synonymous or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • BP7 criteria do not apply.
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.993C>A
Protein (HGVS p.)
NP_000305.3:p.(Asp331Glu)
GRCh38
chr10:87961085 C>A
GRCh37
chr10:89720842 C>A

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 +101 bp
0.000
SpliceAI acceptor gainat -148 bp
0.000
SpliceAI donor lossat -171 bp
0.000
SpliceAI donor gainat +37 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.622
BayesDel
-0.042

How the predictions were used

PP3 REVEL score of 0.622 does not meet the VCEP PP3 threshold of >0.7. BayesDel score of -0.042 does not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.622 (threshold >0.7 not met).
  • BayesDel score = -0.042 (does not support deleterious effect).
  • SpliceAI max delta = 0.00.
Sources
revelbayesdelspliceai ↗cspec ↗
BP4 REVEL score of 0.622 is not <0.5, failing the VCEP BP4 threshold for missense variants. Multiple computational lines do not consistently suggest no impact. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.622 (threshold <0.5 not met).
  • BayesDel score = -0.042 (near zero
  • indeterminate).
Sources
revelbayesdelspliceai ↗cspec ↗
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 applies only to synonymous or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • BP7 criteria do not apply.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.622. BayesDel score = -0.0419274.

3 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.
    Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. NM_000314.8:c.993C>A (p.Asp331Glu) was not identified in this paper.
    Does not name this variant
    PMID 10866302 ↗
  • Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor.
    Investigates the C2 domain of PTEN for protein stabilization and membrane positioning. NM_000314.8:c.993C>A (p.Asp331Glu) was not identified in this paper.
    Does not name this variant
    PMID 11156408 ↗
  • The determinants of head and neck cancer: Unmasking the PI3K pathway mutations.
    Reviews PI3K/PTEN/mTOR pathway mutations in head and neck squamous cell carcinoma. Discusses p.D331G at the C2 domain as a recurrent HNSCC mutation but does not describe p.Asp331Glu (c.993C>A). The queried variant is not reported.
    Does not name this variant
    PMID 25126449 ↗
    Quoted passage
    recurrent mutations were also found in exon 8, resulting in p.D331G at the C2 domain

    PTEN mutations section; Figure 2A; Table 1

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 0.000 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 = 0.00). REVEL score = 0.622. BayesDel score = -0.0419274.

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.