About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.1211G>T, p.(Ter404LeuextTer8)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000314.8:c.1211G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%) in large sequenced populations.
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: PM2 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.
No screenshot for this evidence
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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 ↗
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64296267, n = 2 times).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 12 not met · 0 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000314.8:c.1211G>T (p.Ter404LeuextTer8) is a stop-loss variant in PTEN that removes the native stop codon and extends the protein by 8 amino acids. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under the PTEN VCEP v3.2.
The variant is absent from ClinVar. It has been reported in COSMIC (COSV64296267) in two somatic cancer samples, but no germline disease associations have been established.
No functional data is available for this stop-loss variant. The PTEN VCEP PVS1 decision tree does not cover stop-loss variants (limited to nonsense, frameshift, splice site, and exon deletions). The Mighell et al. 2018 phosphatase saturation mutagenesis assay evaluates missense substitutions only and does not include stop-loss variants.
No de novo observations, segregation data, or case-control studies are available. No publications were identified that mention this specific variant.
With only PM2_Supporting met (absent from population databases) and all other criteria either not met or not applicable, this variant does not reach any classification threshold under the PTEN VCEP v3.2 combination rules and remains a Variant of Uncertain Significance (VUS). Notably, PM4 (protein extension from stop-loss) is flagged for human review — the VCEP PM4 rule explicitly covers stop-loss variants causing protein extension, and if applied at Moderate strength, the combination of PM4 + PM2_Supporting could support Likely Pathogenic under certain rule configurations.
No criteria match.
Met · 1
PM2 SupportingNM_000314.8:c.1211G>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.00001 (0.001%) in large sequenced populations. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No same amino acid change previously established as pathogenic has been identified at this position. The variant is absent from ClinVar, and no stop-loss variant at p.Ter404 with a different nucleotide change has been reported as pathogenic. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no pathogenic comparator exists at the same amino acid position.
Still missing
- No ClinVar entries for any stop-loss variant at p.Ter404.
Sources
PS2 No de novo observations have been reported for this variant. The literature search yielded no publications, and no de novo data is available in ClinVar or other curated sources. Details ▾Hide ▴
Evidence considered
- No de novo observations identified in ClinVar or literature.
Still missing
- No proband or family data available to assess de novo status.
Sources
PS4 No proband counts or phenotype specificity scores are available. The variant is absent from ClinVar and no affected individuals have been reported in the literature. PS4 requires proband enumeration with specificity scoring per the PTEN VCEP, and no such data exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband data available for PS4 proband counting or specificity scoring.
Still missing
- No proband or case-control data available.
Sources
PM1 The PTEN VCEP defines PM1 for residues in three catalytic motifs: WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) per NP_000305.3. Position 404 is the native stop codon at the extreme C-terminus, far downstream of all defined catalytic motifs. No mutational hotspot at this position has been identified (cancerhotspots.org: not significant). Details ▾Hide ▴
Evidence considered
- Residue 404 is not within the VCEP-defined catalytic motifs (90-94
- 123-130
- 166-168).
- Not a significant mutational hotspot.
Sources
PM6 No de novo observations (assumed or confirmed) have been reported for this variant. The literature search yielded no publications, and no de novo data is present in ClinVar. Details ▾Hide ▴
Evidence considered
- No de novo observations identified.
Still missing
- No de novo data available.
Sources
PP1 No co-segregation data is available. The variant is absent from ClinVar and no family studies have been published. The PTEN VCEP requires at least 3-4 meioses for PP1 at supporting strength. Details ▾Hide ▴
Evidence considered
- No segregation data available
- variant absent from ClinVar.
Still missing
- No family or segregation data.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0). The PTEN VCEP BA1 threshold requires a filtering allele frequency >0.00056 (0.056%), which is not met. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0 across all gnomAD datasets
- BA1 threshold >0.056% not met.
Sources
BS1 The variant is absent from gnomAD (allele frequency = 0). The PTEN VCEP BS1 threshold requires a filtering allele frequency ≥0.0000043 (0.00043%) for BS1_Supporting or ≥0.000043 (0.0043%) for BS1, neither of which is met. Details ▾Hide ▴
Evidence considered
- Allele frequency 0.0 across all gnomAD datasets
- BS1 thresholds not met.
Sources
BS2 No homozygous observations of this variant have been reported in healthy or PHTS-unaffected individuals. The variant is absent from gnomAD, and no homozygous data exists in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- no homozygous observations.
Still missing
- No homozygous data available.
Sources
BS4 No segregation data is available to assess lack of segregation in affected family members. The PTEN VCEP requires lack of segregation in one family for BS4_Supporting or two or more families for BS4. Details ▾Hide ▴
Evidence considered
- No segregation data available
- variant absent from ClinVar.
Still missing
- No family segregation data.
Sources
BP2 No observations of this variant in trans with a pathogenic or likely pathogenic PTEN variant, nor in cis/unknown phase with different pathogenic PTEN variants, have been reported. The variant is absent from ClinVar and population databases. Details ▾Hide ▴
Evidence considered
- No trans or cis phase observations with pathogenic PTEN variants identified.
Still missing
- No phase data available.
Sources
BP5 No cases have been identified where this variant was found in an individual with an alternate molecular basis for disease. The PTEN VCEP requires at least two such cases for BP5 application. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis cases identified.
Still missing
- No alternate diagnosis data available.
Sources
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000314.8:c.1211G>T is a stop-loss variant (p.Ter404LeuextTer8) that removes the native stop codon and extends the protein by 8 amino acids. The PTEN VCEP PVS1 decision tree covers nonsense, frameshift, canonical splice site disruptions, and single/multi-exon deletions — stop-loss is not a null variant mechanism and is not included in the decision tree. Protein extension from stop-loss is addressed under PM4 in the VCEP framework. Details ▾Hide ▴
Evidence considered
- Stop-loss variant p.(Ter404LeuextTer8) is not a null variant under the PTEN PVS1 decision tree (which covers nonsense
- frameshift
- canonical splice
- and exon deletions only).
Sources
PS3 N/AThe PTEN VCEP PS3 criteria apply to splicing assay data (PS3_Strong) and missense variant phosphatase activity per Mighell et al. 2018 (PS3_Moderate, Cum_score ≤ -1.11). This is a stop-loss variant (p.Ter404LeuextTer8), not a missense change, and the Mighell saturation mutagenesis dataset (mmc2.xlsx, Table S2) only covers internal missense substitutions and nonsense variants. The variant is not present in the functional assay data. No splicing impact is predicted (SpliceAI max delta = 0.01). Details ▾Hide ▴
Evidence considered
- Stop-loss variant not evaluated in Mighell et al. phosphatase assay (missense-only dataset).
- SpliceAI predicts no splicing impact (max delta 0.01).
Still missing
- No functional assay data for stop-loss variants at the PTEN C-terminus.
Sources
PM3 VCEPPM3 is not applicable to PTEN per the VCEP. PTEN hamartoma tumor syndrome is an autosomal dominant disorder; PM3 applies to recessive disorders with trans phase detection. Details ▾Hide ▴
Evidence considered
- PM3 is marked Not Applicable by the PTEN Expert Panel (autosomal dominant disorder).
Sources
PM4 N/APM4 is pre-triaged as trivially not_applicable. Note: NM_000314.8:c.1211G>T is a stop-loss variant causing protein extension (p.Ter404LeuextTer8), which is explicitly covered by the PTEN VCEP PM4 rule ('variants causing protein extension'). The user has directed that PM4 be skipped; if reassessed, PM4_Moderate would apply. Details ▾Hide ▴
Evidence considered
- Pre-triaged as not_applicable per user instruction. VCEP PM4 rule does cover protein extension from stop-loss variants.
Still missing
- User override: PM4 marked as trivially not_applicable despite VCEP inclusion of stop-loss under PM4.
Sources
PM5 N/AThe PTEN VCEP PM5 rule applies to missense changes at an amino acid residue where a different missense change has been classified as pathogenic or likely pathogenic. NM_000314.8:c.1211G>T is a stop-loss variant (p.Ter404LeuextTer8), not a missense substitution. There is no reference amino acid at position 404 for missense comparison (the reference is a stop codon). Details ▾Hide ▴
Evidence considered
- Variant class is stop-loss
- not missense — PM5 framework requires missense comparator at same residue.
Sources
cspec ↗pm5_candidates
PP2 N/AThe PTEN VCEP PP2 criterion applies to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.1211G>T is a stop-loss variant, not a missense substitution. PP2 is not applicable to non-missense variant types. Details ▾Hide ▴
PP3 N/AThe PTEN VCEP PP3 criterion applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL >0.7). This is a stop-loss variant. SpliceAI predicts no splicing impact (max delta = 0.01). REVEL score is not available for this variant. BayesDel score (-0.375) is not included in the VCEP PP3 rules. No applicable computational evidence tier exists for stop-loss variants under the VCEP PP3 specification. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 — no splicing impact.
- REVEL not available for this variant.
- BayesDel -0.375 — not defined in VCEP PP3 rules.
Still missing
- No VCEP-defined computational evidence tier for stop-loss variants.
Sources
PP4 VCEPThe PTEN VCEP specifies that PP4 is Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications (Use 2). Details ▾Hide ▴
PP5 VCEPPP5 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The PTEN VCEP explicitly prohibits use of PP5. Details ▾Hide ▴
Evidence considered
- PP5 is explicitly marked Not Applicable for this VCEP by the PTEN Expert Panel.
Sources
BS3 N/AThe PTEN VCEP BS3_Strong applies to intronic or synonymous variants with splicing assays showing no impact. BS3_Supporting applies to the Mighell et al. 2018 phosphatase assay (Cum_score >0). This is a stop-loss variant — not a splicing variant (SpliceAI max delta 0.01) and not evaluated in the Mighell missense assay. The functional data available is not applicable to the BS3 framework for this variant type. Details ▾Hide ▴
Evidence considered
- Stop-loss variant not evaluated in Mighell phosphatase assay (missense-only).
- No splicing impact (SpliceAI max delta 0.01).
Still missing
- No functional data for stop-loss variants at the PTEN C-terminus.
Sources
BP1 VCEPBP1 is explicitly Not Applicable to PTEN per the PTEN VCEP v3.2 specification. Details ▾Hide ▴
BP3 VCEPBP3 (in-frame deletions/insertions in repetitive regions) is not applicable to PTEN per the VCEP. Additionally, this is a single-nucleotide substitution (stop-loss), not an in-frame indel. Details ▾Hide ▴
Evidence considered
- BP3 is not applicable to PTEN and does not apply to substitution variants.
Sources
BP4 N/AThe PTEN VCEP BP4 criterion applies to synonymous or intronic variants (SpliceAI + VarSeak no impact) or missense variants (REVEL <0.5). This is a stop-loss variant. REVEL score is not available. The VCEP BP4 specification does not define computational evidence thresholds for stop-loss variants. Details ▾Hide ▴
Evidence considered
- Stop-loss not covered by VCEP BP4 (synonymous/intronic/missense only).
- REVEL score not available.
Still missing
- No VCEP-defined benign computational evidence tier for stop-loss variants.
Sources
BP6 VCEPBP6 is Not Applicable for this VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The PTEN VCEP explicitly prohibits use of BP6. Details ▾Hide ▴
Evidence considered
- BP6 is explicitly marked Not Applicable for this VCEP by the PTEN Expert Panel.
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact. NM_000314.8:c.1211G>T is a stop-loss variant that alters the protein sequence (p.Ter404LeuextTer8) — it is not synonymous and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is protein-altering (stop-loss)
- not synonymous or intronic.
Sources
PS5 N/APS5 is not a canonical ACMG/AMP criterion code. The standard ACMG/AMP 2015 framework and the PTEN VCEP v3.2 do not include a PS5 criterion. Details ▾Hide ▴
Evidence considered
- PS5 does not exist in the ACMG/AMP 2015 criteria or the PTEN VCEP v3.2 specification.
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.1211G>T
- Protein (HGVS p.)
- NP_000305.3:p.(Ter404LeuextTer8)
- GRCh38
- chr10:87965471 G>T
- GRCh37
- chr10:89725228 G>T
- COSMIC
- COSV64296267
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
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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-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- -0.375
How the predictions were used
PP3 N/AThe PTEN VCEP PP3 criterion applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL >0.7). This is a stop-loss variant. SpliceAI predicts no splicing impact (max delta = 0.01). REVEL score is not available for this variant. BayesDel score (-0.375) is not included in the VCEP PP3 rules. No applicable computational evidence tier exists for stop-loss variants under the VCEP PP3 specification. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 — no splicing impact.
- REVEL not available for this variant.
- BayesDel -0.375 — not defined in VCEP PP3 rules.
Still missing
- No VCEP-defined computational evidence tier for stop-loss variants.
Sources
BP4 N/AThe PTEN VCEP BP4 criterion applies to synonymous or intronic variants (SpliceAI + VarSeak no impact) or missense variants (REVEL <0.5). This is a stop-loss variant. REVEL score is not available. The VCEP BP4 specification does not define computational evidence thresholds for stop-loss variants. Details ▾Hide ▴
Evidence considered
- Stop-loss not covered by VCEP BP4 (synonymous/intronic/missense only).
- REVEL score not available.
Still missing
- No VCEP-defined benign computational evidence tier for stop-loss variants.
Sources
BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing algorithms predict no impact. NM_000314.8:c.1211G>T is a stop-loss variant that alters the protein sequence (p.Ter404LeuextTer8) — it is not synonymous and does not meet BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is protein-altering (stop-loss)
- not synonymous or intronic.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = -0.375297.
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.
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637575
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000314.8%3Ac.1211G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89725228-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87965471-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87965471-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.1211…
- OncoKB ↗www.oncokb.org/gene/PTEN/*404Lext*8
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139203648
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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 = 0.01). BayesDel score = -0.375297.
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 has previously been reported in somatic cancers (COSMIC; COSV64296267, n = 2 times).