0%
PTENc.871_875delLikely pathogenic
Print report
Variant interpretation report

PTEN c.871_875del, p.(Glu291TrpfsTer5)

NM_000314.8:c.871_875del NP_000305.3:p.(Glu291TrpfsTer5) 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

NM_000314.8:c.871_875del is a 5 bp frameshift deletion in exon 8 that produces a premature termination codon at NP_000305.3:p.(Glu291TrpfsTer5), well 5' of the PTEN NMD cutoff at p.D375 (c.1121). Under the PTEN VCEP PVS1 decision tree, frameshift variants with a stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 that are predicted to undergo NMD are assigned PVS1 at very strong strength.

PM2Supporting
PM2 · supporting

NM_000314.8:c.871_875del 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%).

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 Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 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.

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

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.

28 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 13 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.871_875del is a 5 bp frameshift deletion in PTEN exon 8 that produces a premature termination codon at p.(Glu291TrpfsTer5), located 5' of the NMD boundary at p.D375, and is predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the PTEN VCEP v3.2.0 decision tree.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (0 alleles across all populations), meeting the PTEN VCEP PM2_Supporting criterion (allele frequency <0.00001).

The variant is absent from ClinVar and has not been reported in the published literature as a germline observation; no proband counts (PS4), de novo events (PS2/PM6), segregation data (PP1/BS4), or functional assay results (PS3/BS3) are available.

OncoKB curates this variant as Likely Oncogenic with a Likely Loss-of-function biological effect, consistent with the predicted frameshift mechanism, though this somatic cancer annotation does not directly constitute germline ACMG/AMP evidence.

SpliceAI predicts no cryptic splice impact (max delta score 0.03); the variant is not located in a PTEN catalytic motif (PM1 not met: residue 291 is outside motifs at 90-94, 123-130, 166-168).

Of the 27 criteria assessed, two are met: PVS1 (very_strong) and PM2_Supporting. Under the PTEN VCEP v3.2.0 combination rules, PVS1 alone does not directly satisfy any single-rule Pathogenic or Likely Pathogenic inference without at least one additional Moderate or Strong criterion, or two Supporting criteria. The combination of 1 Very Strong + 1 Supporting does not match any VCEP rule. Per the adjudication framework, when the VCEP rules do not produce a classification, the generic ACMG/AMP 2015 framework (PMID:25741868) is applied as fallback: a null variant (frameshift) in a gene where loss of function is a well-established disease mechanism meets PVS1 at very strong strength, which alone is sufficient for a Pathogenic classification under generic rules.

Met · 2

PVS1 Very strongNM_000314.8:c.871_875del is a 5 bp frameshift deletion in exon 8 that produces a premature termination codon at NP_000305.3:p.(Glu291TrpfsTer5), well 5' of the PTEN NMD cutoff at p.D375 (c.1121). Under the PTEN VCEP PVS1 decision tree, frameshift variants with a stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 that are predicted to undergo NMD are assigned PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion c.871_875del creates premature stop at codon 295
  • Stop codon is 5' to p.D375 (c.1121) NMD boundary
  • Predicted to undergo nonsense-mediated decay
  • PTEN loss of function is an established disease mechanism (PTEN VCEP v3.2.0)
Sources
vcep_pvs1_decisiontree_ptencspec ↗pvs1_generic_framework ↗
PM2 SupportingNM_000314.8:c.871_875del 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%). 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 ↗

Not met · 13 · evaluated, threshold not reached

PS2 No de novo observations of NM_000314.8:c.871_875del have been identified in ClinVar, the published literature, or any other source reviewed. Details ▾Hide ▴
Evidence considered
  • No de novo reports found in ClinVar or literature
Still missing
  • De novo status could be investigated if parental samples are available
PS3 No well-established functional data are available for this frameshift variant. The PTEN VCEP PS3_Moderate rule (Mighell et al. 2018 phosphatase assay) applies only to missense variants. The two publications identified (PMID:11237521, PMID:17218262) are general functional reviews of PTEN that do not mention or assay this specific variant. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 functional assay is missense-only
  • not applicable to frameshift variants
  • No RNA/mini-gene splicing assay data available
  • PMID:11237521 and PMID:17218262 are general PTEN reviews without variant-specific data
Still missing
  • Targeted functional assay for this specific frameshift could provide evidence
Sources
1123752117218262
PS4 No proband observations with PHTS phenotype and this variant have been identified. The variant is absent from ClinVar, and no published case reports or case series describe NM_000314.8:c.871_875del in affected individuals. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • No published probands identified
Still missing
  • Case-level data from clinical laboratories may exist outside ClinVar
PM1 The variant alters codon 291 (p.Glu291). The PTEN VCEP defines catalytic motif hotspots as residues 90-94 (WPD loop), 123-130 (P-loop), and 166-168 (TI-loop) of NP_000305.3. Codon 291 lies outside all three catalytic motifs. Details ▾Hide ▴
Evidence considered
  • p.Glu291 is not within catalytic motifs (90-94
  • 123-130
  • 166-168 per NP_000305.3)
Sources
cspec ↗
PM6 No assumed de novo observations of NM_000314.8:c.871_875del have been identified. The PTEN VCEP requires at minimum one assumed de novo occurrence in a proband with disease and no family history for PM6 at moderate strength; no such observations are available. Details ▾Hide ▴
Evidence considered
  • No assumed de novo reports in ClinVar or literature
Still missing
  • Parental testing could reveal de novo status
PP1 No co-segregation data are available for NM_000314.8:c.871_875del. The PTEN VCEP requires at minimum 3-4 meioses for PP1 at supporting strength; no segregation studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • Family testing could provide segregation evidence
BA1 BA1 requires a gnomAD filtering allele frequency >0.00056 (0.056%) per the PTEN VCEP. NM_000314.8:c.871_875del is absent from gnomAD v2.1 and v4.1 and does not meet this threshold. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 BS1 requires a gnomAD filtering allele frequency between 0.0000043 (0.00043%) and 0.00056 (0.056%) per the PTEN VCEP. NM_000314.8:c.871_875del is absent from all gnomAD populations and does not meet any BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Variant absent from gnomAD v2.1 and v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS2 BS2 requires observation in a homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations of NM_000314.8:c.871_875del have been identified in gnomAD or any other source; the variant is entirely absent from population databases. Details ▾Hide ▴
Evidence considered
  • No homozygous observations in gnomAD (0 homozygotes)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating a benign effect have been reported for this variant. The PTEN VCEP BS3_Supporting rule (Mighell et al. 2018 phosphatase activity >0) applies only to missense variants and cannot be assessed for this frameshift. No RNA or mini-gene splicing assays showing no impact are available. PMID:11237521 and PMID:17218262 are general PTEN reviews without variant-specific functional data. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 functional assay is missense-only
  • No splicing assay data available
  • PubMed abstracts reviewed do not mention this variant
Still missing
  • Functional studies specific to this variant could clarify effect
Sources
1123752117218262
BS4 No segregation data are available to assess lack of segregation in affected family members. The PTEN VCEP requires lack of segregation in affected members of two or more families for BS4 at strong strength, or one family for supporting strength. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • Family segregation studies could provide evidence
BP2 No observations of NM_000314.8:c.871_875del in trans with a pathogenic or likely pathogenic PTEN variant have been reported, nor are there three or more observations in cis or unknown phase with different pathogenic PTEN variants. The variant is absent from ClinVar and population databases, precluding any phase analysis. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no phase observations available
Still missing
  • Clinical testing could reveal phase relationships
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observations have been reported for NM_000314.8:c.871_875del. The PTEN VCEP further requires at least two such cases and that the other gene/disorder be highly penetrant with no phenotypic overlap with PTEN. Details ▾Hide ▴
Evidence considered
  • No cases with alternate molecular basis identified
Still missing
  • Clinical co-occurrence data could identify alternate diagnoses
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid change as a known pathogenic variant. This variant is a frameshift deletion, not a missense substitution, and does not produce a previously described pathogenic amino acid change. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants causing protein length changes. NM_000314.8:c.871_875del is an out-of-frame (frameshift) deletion, not an in-frame deletion, and does not meet PM4 criteria under the PTEN VCEP specification. Details ▾Hide ▴
Evidence considered
  • Variant is a frameshift (out-of-frame) deletion
  • not in-frame
Sources
cspec ↗
PM5 N/APM5 applies to missense variants at an amino acid residue where a different pathogenic missense change has been described. This variant is a frameshift deletion, not a missense change, and is ineligible for PM5 assessment. Details ▾Hide ▴
Evidence considered
  • Variant is frameshift
  • not missense
  • PM5 not applicable
Sources
cspec ↗
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.871_875del is a frameshift variant, not a missense variant. Details ▾Hide ▴
Evidence considered
  • Variant is frameshift
  • not missense
  • PP2 not applicable
Sources
cspec ↗
PP3 N/AUnder the PTEN VCEP, PP3 applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift variant; SpliceAI predicts no significant splice impact (max delta score = 0.03) and REVEL is not applicable to non-SNVs. The VCEP does not define a PP3 pathway for frameshift variants. Details ▾Hide ▴
Evidence considered
  • Frameshift variant
  • VCEP PP3 pathway defined for splicing/missense only
  • SpliceAI max delta = 0.03 (no splice impact)
Sources
cspec ↗spliceai ↗
PP4 VCEPPP4 is designated as Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the PS4 rule specifications instead. Details ▾Hide ▴
Evidence considered
  • PP4 not for use per PTEN VCEP
  • phenotype specificity folded into PS4
Sources
cspec ↗
PP5 VCEPPP5 is designated as Not Applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee policy. This criterion is not for use in PTEN variant interpretation. Details ▾Hide ▴
Evidence considered
  • Criterion not for use per ClinGen VCEP policy
Sources
cspec ↗
BP1 VCEPBP1 (missense variant in a gene where primarily truncating variants cause disease) is designated as Not Applicable to PTEN by the VCEP. PTEN has both missense and truncating pathogenic variants as common disease mechanisms. Details ▾Hide ▴
Evidence considered
  • BP1 not applicable to PTEN per VCEP specification
Sources
cspec ↗
BP3 VCEPBP3 (in-frame deletions/insertions in a repetitive region without known function) is designated as Not Applicable to PTEN by the VCEP. Details ▾Hide ▴
Evidence considered
  • BP3 not applicable to PTEN per VCEP specification
Sources
cspec ↗
BP4 N/AUnder the PTEN VCEP, BP4 applies to synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or missense variants with REVEL <0.5. NM_000314.8:c.871_875del is a frameshift variant and does not fall within the VCEP-defined scope for BP4. Details ▾Hide ▴
Evidence considered
  • Frameshift variant
  • BP4 VCEP scope is synonymous/intronic/missense only
Sources
cspec ↗
BP6 VCEPBP6 (reputable source reports variant as benign without available evidence) is designated as Not Applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee policy. Details ▾Hide ▴
Evidence considered
  • Criterion not for use per ClinGen VCEP policy
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.871_875del is a frameshift coding deletion and is not a synonymous or deep intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is a frameshift coding deletion
  • not synonymous/intronic
Sources
cspec ↗
PS5 N/APS5 (reputable source reports variant as pathogenic without available evidence) is equivalent to PP5 in the PTEN VCEP framework, which is explicitly marked as not for use per ClinGen Sequence Variant Interpretation VCEP Review Committee policy. Details ▾Hide ▴
Evidence considered
  • Criterion not for use per ClinGen VCEP policy
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.871_875del
Protein (HGVS p.)
NP_000305.3:p.(Glu291TrpfsTer5)
GRCh38
chr10:87960961 TAGAAA>T
GRCh37
chr10:89720718 TAGAAA>T

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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +233 bp
0.000
SpliceAI acceptor gainat -24 bp
0.010
SpliceAI donor lossat -47 bp
0.010
SpliceAI donor gainat -2 bp
0.030
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/AUnder the PTEN VCEP, PP3 applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift variant; SpliceAI predicts no significant splice impact (max delta score = 0.03) and REVEL is not applicable to non-SNVs. The VCEP does not define a PP3 pathway for frameshift variants. Details ▾Hide ▴
Evidence considered
  • Frameshift variant
  • VCEP PP3 pathway defined for splicing/missense only
  • SpliceAI max delta = 0.03 (no splice impact)
Sources
cspec ↗spliceai ↗
BP4 N/AUnder the PTEN VCEP, BP4 applies to synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or missense variants with REVEL <0.5. NM_000314.8:c.871_875del is a frameshift variant and does not fall within the VCEP-defined scope for BP4. Details ▾Hide ▴
Evidence considered
  • Frameshift variant
  • BP4 VCEP scope is synonymous/intronic/missense only
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.871_875del is a frameshift coding deletion and is not a synonymous or deep intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is a frameshift coding deletion
  • not synonymous/intronic
Sources
cspec ↗

Statement

In silico

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

2 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

  • PTEN: life as a tumor suppressor.
    No paper-specific finding is recorded.
    PMID 11237521 ↗
  • Essential role for nuclear PTEN in maintaining chromosomal integrity.
    No paper-specific finding is recorded.
    PMID 17218262 ↗

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.

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

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.