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PTENc.955_956dupLikely pathogenic
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Variant interpretation report

PTEN c.955_956dup, p.(Thr321Ter)

NM_000314.8:c.955_956dup NP_000305.3:p.(Thr321Ter) 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.

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
PVS1Very strong
PVS1 · very strong

Using the PTEN-specific PVS1 decision tree, NM_000314.8:c.955_956dup is a null variant that introduces a premature termination codon at p.(Thr321Ter), which is 5' of the PTEN NMD cutoff at p.D375 (c.1121); this supports PVS1 at Very Strong strength.

PM2Supporting
PM2 · supporting

The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting rule for an ultra-rare or absent allele in population databases.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Applied the explicit PTEN CSPEC/VCEP final-classification framework from final_classification_framework.json (cspec_ruleset criteria-combination framework), not generic ACMG combination rules.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 3 not met · 13 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The PTEN c.955_956dup (p.Thr321Ter; p.T321*) variant has not been observed in somatic cancers in COSMIC, has not been reported in ClinVar, and is listed by OncoKB as Likely Oncogenic with a likely loss-of-function effect.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PTEN PM2 at Supporting strength.

PTEN-specific null-variant guidance supports PVS1 at Very Strong strength because this duplication introduces a premature termination codon at p.Thr321, which is upstream of the PTEN p.D375 (c.1121) NMD cutoff in transcript NM_000314.8.

SpliceAI predicts no significant splice effect for NM_000314.8:c.955_956dup (max delta score 0.01), and the residue is outside the PTEN PM1 catalytic motifs with no Cancer Hotspots signal at T321.

Met · 2

PVS1 Very strongUsing the PTEN-specific PVS1 decision tree, NM_000314.8:c.955_956dup is a null variant that introduces a premature termination codon at p.(Thr321Ter), which is 5' of the PTEN NMD cutoff at p.D375 (c.1121); this supports PVS1 at Very Strong strength. Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree.
Evidence considered
  • NM_000314.8:c.955_956dup normalizes to NP_000305.3:p.(Thr321Ter) / p.(T321*)
  • PTEN PVS1 decision tree assigns PVS1 to stop codons or disruption at or 5' to p.D375 (c.1121) in NM_000314.8
Sources
cspec ↗vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PM2 SupportingThe variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting rule for an ultra-rare or absent allele in population databases. Details ▾Hide ▴
Rule
Absent in population databases or present below the PTEN PM2 threshold; PTEN specification uses Supporting strength.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 3 · evaluated, threshold not reached

PM1 PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168. The observed stop at residue 321 lies outside these motifs, and Cancer Hotspots found no significant hotspot at T321. Details ▾Hide ▴
Rule
Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).
Evidence considered
  • PM1 catalytic motifs are residues 90-94, 123-130, and 166-168
  • Cancer Hotspots search for PTEN T321 found no hotspot row
Sources
cspec ↗hotspots1123752117218262
BA1 The variant is absent from gnomAD and therefore does not meet the PTEN BA1 population threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD and does not reach the PTEN BS1 supporting or strong frequency ranges. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS1 No prior pathogenic variant with the same amino acid change or qualifying same-nucleotide pathogenic splice comparator was documented in the reviewed workspace. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result for this variant
Still missing
  • No qualifying prior pathogenic comparator identified in reviewed sources
Sources
cspec ↗clinvar ↗
PS2 No confirmed de novo observation with maternity and paternity confirmation was present in the workspace. Details ▾Hide ▴
Still missing
  • No case-level parental testing/segregation data in workspace
Sources
cspec ↗
PS3 No variant-specific functional study meeting PTEN PS3 rules was identified. The indexed Mighell assay file is designated for missense variants, and no RNA/minigene splicing assay for this duplication was provided. Details ▾Hide ▴
Evidence considered
  • PTEN mmc2 functional assay guidance is for missense variants
Still missing
  • No variant-specific RNA/minigene or other qualifying functional assay in workspace
Sources
cspec ↗vcep_m_m_c_21123752117218262
PS4 No proband-count, phenotype-specificity score, or case-control enrichment data sufficient for PTEN PS4 were assembled in the workspace. Details ▾Hide ▴
Evidence considered
  • ClinVar search returned no result
  • COSMIC search returned no result
Still missing
  • No qualifying affected-proband or case-control evidence in workspace
Sources
cspec ↗clinvar ↗cosmic
PM6 No assumed de novo observation without parental confirmation was documented in the workspace. Details ▾Hide ▴
Still missing
  • No case-level de novo evidence in workspace
Sources
cspec ↗
PP1 No segregation data across informative meioses were provided for PP1 assessment. Details ▾Hide ▴
Still missing
  • No family segregation data in workspace
Sources
cspec ↗
PP3 PTEN PP3 requires concordant splicing predictors for qualifying splicing variants or REVEL >0.7 for missense variants. This workspace only showed SpliceAI with no significant splice impact and no qualifying VarSeak/REVEL evidence for PP3 application. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • REVEL was skipped/not available for this non-SNV
Still missing
  • No PTEN-qualifying predictor combination for PP3 in workspace
Sources
cspec ↗spliceai ↗
BS2 No homozygous observations in healthy or PTEN-hamartoma-spectrum-unaffected individuals were provided. Details ▾Hide ▴
Still missing
  • No qualifying unaffected homozygote observations in workspace
Sources
cspec ↗
BS3 No variant-specific functional evidence showing no damaging effect was identified. The indexed Mighell assay is for missense variants, and no no-effect RNA/splicing assay for this duplication was provided. Details ▾Hide ▴
Evidence considered
  • PTEN mmc2 functional assay guidance is for missense variants
Still missing
  • No qualifying benign functional assay in workspace
Sources
cspec ↗vcep_m_m_c_21123752117218262
BS4 No segregation dataset demonstrating lack of segregation in one or more families was present. Details ▾Hide ▴
Still missing
  • No family segregation data in workspace
Sources
cspec ↗
BP2 No phase data or observations with other pathogenic/likely pathogenic PTEN variants were assembled for BP2 assessment. Details ▾Hide ▴
Still missing
  • No cis/trans or phase information in workspace
Sources
cspec ↗
BP4 PTEN BP4 requires concordant benign splicing prediction for qualifying splicing variants or REVEL <0.5 for missense variants. The workspace only provides SpliceAI and no VarSeak result, and the variant is not a missense substitution. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • No VarSeak result provided
  • REVEL not available for this non-SNV
Still missing
  • No PTEN-qualifying predictor combination for BP4 in workspace
Sources
cspec ↗spliceai ↗
BP5 No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping phenotype was assembled. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data in workspace
Sources
cspec ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable for PTEN per the VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
PM4 N/APTEN PM4 applies to in-frame insertions/deletions affecting defined regions or to stop-loss/protein-extension variants. This variant introduces a premature stop codon rather than an in-frame length change or stop-loss. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr321Ter)
Sources
cspec ↗
PM5 N/APM5 is a missense-residue criterion and does not apply to a truncating variant. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr321Ter)
Sources
cspec ↗
PP2 N/APP2 is a missense criterion and does not apply to this truncating variant. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr321Ter)
Sources
cspec ↗
PP4 N/APP4 is marked not applicable by the PTEN VCEP because phenotype specificity is incorporated into PS4 usage. Details ▾Hide ▴
Sources
cspec ↗
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
BP1 N/ABP1 is marked not applicable by the PTEN VCEP. Details ▾Hide ▴
Sources
cspec ↗
BP3 N/ABP3 is not applicable to PTEN per the VCEP specification. Details ▾Hide ▴
Sources
cspec ↗
BP6 N/ABP6 is not for use in this VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 is limited to synonymous or qualifying intronic variants and does not apply to this truncating exonic duplication. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr321Ter)
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.955_956dup
Protein (HGVS p.)
NP_000305.3:p.(Thr321Ter)
GRCh38
chr10:87961046 T>TAC
GRCh37
chr10:89720803 T>TAC

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

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 PTEN PP3 requires concordant splicing predictors for qualifying splicing variants or REVEL >0.7 for missense variants. This workspace only showed SpliceAI with no significant splice impact and no qualifying VarSeak/REVEL evidence for PP3 application. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • REVEL was skipped/not available for this non-SNV
Still missing
  • No PTEN-qualifying predictor combination for PP3 in workspace
Sources
cspec ↗spliceai ↗
BP4 PTEN BP4 requires concordant benign splicing prediction for qualifying splicing variants or REVEL <0.5 for missense variants. The workspace only provides SpliceAI and no VarSeak result, and the variant is not a missense substitution. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • No VarSeak result provided
  • REVEL not available for this non-SNV
Still missing
  • No PTEN-qualifying predictor combination for BP4 in workspace
Sources
cspec ↗spliceai ↗
BP7 N/ABP7 is limited to synonymous or qualifying intronic variants and does not apply to this truncating exonic duplication. Details ▾Hide ▴
Evidence considered
  • Protein consequence is p.(Thr321Ter)
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record
Cancer hotspots Captured Cancer Hotspots source record
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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

Somatic

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