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PTENc.923delLikely pathogenic
Print report
Variant interpretation report

PTEN c.923del, p.(Arg308LeufsTer9)

NM_000314.8:c.923del NP_000305.3:p.(Arg308LeufsTer9) 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. 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.923del is a frameshift deletion in exon 8 producing a premature termination codon at p.(Arg308LeufsTer9). The new stop codon at position 316 lies 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay (NMD). Exon 8 is present in the biologically-relevant transcript NM_000314.8. Under the PTEN VCEP PVS1 decision tree, a frameshift variant with stop codon 5' to p.D375 predicted to undergo NMD in a biologically-relevant transcript is assigned PVS1.

PM2Supporting
PM2 · supporting

NM_000314.8:c.923del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under PTEN VCEP, PM2_Supporting is applied when allele frequency is < 0.00001 (0.001%) in gnomAD or another large sequenced population.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 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
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. 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
7 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64291945, n = 7 times).

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, 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.923del is a frameshift deletion in PTEN exon 8 resulting in a premature termination codon at p.Arg308LeufsTer9, which lies 5' to the p.D375 threshold and is predicted to undergo NMD, meeting PVS1 under the PTEN VCEP decision tree.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under PTEN VCEP (allele frequency < 0.001%).

Under the PTEN VCEP combination rules (Version 3.2), PVS1 alone with PM2_Supporting does not satisfy any pathogenic or likely pathogenic classification rule. The variant has not been reported in ClinVar, has no de novo observations, no co-segregation data, and no variant-specific functional data.

This variant has been observed in 7 somatic cancer samples (COSMIC: COSV64291945), and OncoKB classifies it as Likely Oncogenic with a predicted loss-of-function effect, consistent with PTEN's tumor suppressor role. However, somatic observations do not directly contribute to germline ACMG/AMP classification under the PTEN VCEP.

Met · 2

PVS1 Very strongNM_000314.8:c.923del is a frameshift deletion in exon 8 producing a premature termination codon at p.(Arg308LeufsTer9). The new stop codon at position 316 lies 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay (NMD). Exon 8 is present in the biologically-relevant transcript NM_000314.8. Under the PTEN VCEP PVS1 decision tree, a frameshift variant with stop codon 5' to p.D375 predicted to undergo NMD in a biologically-relevant transcript is assigned PVS1. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion in exon 8 of 9 exons
  • Premature termination codon at p.Arg308LeufsTer9 (position 316)
  • 5' to p.D375 threshold (position 375)
  • Predicted to undergo NMD
  • Exon 8 is present in biologically-relevant transcript NM_000314.8 (MANE Select)
  • PTEN loss-of-function is an established disease mechanism for PTEN hamartoma tumor syndrome (autosomal dominant)
Sources
vcep_pvs1_decisiontree_ptenpvs1_generic_framework ↗
PM2 SupportingNM_000314.8:c.923del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under PTEN VCEP, PM2_Supporting is applied when allele frequency is < 0.00001 (0.001%) in gnomAD or another large sequenced population. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 13 · evaluated, threshold not reached

PS2 No de novo observation reported in ClinVar, the literature, or any database. Under PTEN VCEP, PS2 requires a confirmed de novo observation in a patient with disease and no family history. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no de novo submissions identified
Still missing
  • No de novo ascertainment data available
PS3 PTEN VCEP specifies PS3_Moderate for phosphatase activity ≤ -1.11 per Mighell et al. 2018 (PMID: 29706350), which applies only to missense variants. The mmc2.xlsx saturation mutagenesis dataset covers missense variants exclusively. This is a frameshift deletion; no variant-specific functional data from RNA assay, mini-gene, or other splicing/functional assay is available. The two publications in the literature packet (PMID: 11237521, PMID: 17218262) are gene-level functional reviews that do not mention NM_000314.8:c.923del. Details ▾Hide ▴
Evidence considered
  • Frameshift variant not evaluable by Mighell et al. 2018 phosphatase activity assay (missense-only dataset)
  • No RNA or mini-gene splicing assay data available
  • No variant-specific functional study found in literature
Still missing
  • No variant-specific functional characterization available
PS4 No probands with specificity scores available for this variant. The variant is absent from ClinVar and no case-control studies or clinical cohorts reporting this variant were identified. Under PTEN VCEP, PS4 requires probands with specificity scores ≥ 1 for any strength level. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • No proband or case-control data available
Still missing
  • No proband or observational data available for this variant
PM1 PTEN VCEP defines PM1 for residues in catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3). The variant affects codon 308 (p.Arg308LeufsTer9), which lies outside these defined catalytic motifs. Although the frameshift truncates the C-terminal C2 domain and PDZ-binding motif, the VCEP specification limits PM1 to the three catalytic motif regions. Details ▾Hide ▴
Evidence considered
  • Residue 308 is not within catalytic motifs 90-94
  • 123-130
  • or 166-168 as defined by PTEN VCEP
  • cancerhotspots.org reports no statistically significant hotspot at this residue
Sources
cspec ↗
PM6 No assumed or confirmed de novo observations identified in ClinVar, the literature, or any database. Under PTEN VCEP, PM6 requires at least one assumed de novo observation in a proband with disease and no family history. Details ▾Hide ▴
Evidence considered
  • No de novo observations in ClinVar or literature
Still missing
  • No de novo ascertainment data available
PP1 No co-segregation data available for this variant. Under PTEN VCEP, PP1 requires at least 3-4 meioses for supporting-level evidence. Details ▾Hide ▴
Evidence considered
  • No co-segregation data available
Still missing
  • No familial segregation data available
BA1 PTEN VCEP applies BA1 when gnomAD filtering allele frequency exceeds 0.00056 (0.056%). This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD
  • allele frequency is 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 PTEN VCEP applies BS1_Strong at AF 0.000043-0.00056 and BS1_Supporting at AF 0.0000043-0.000043. This variant is absent from gnomAD (AF = 0). Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD
  • allele frequency is 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 PTEN VCEP applies BS2 when the variant is observed in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations have been reported for this variant in any population database. Details ▾Hide ▴
Evidence considered
  • No homozygous observations in gnomAD or other population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 PTEN VCEP specifies BS3 for functional studies showing no damaging effect. BS3_Supporting applies for phosphatase activity > 0 per Mighell et al. 2018 (missense variants only). This is a frameshift deletion; no functional data demonstrating no damaging effect is available. Details ▾Hide ▴
Evidence considered
  • Frameshift variant not evaluable by Mighell et al. 2018 phosphatase activity assay (missense-only dataset)
  • No functional data demonstrating no damaging effect
Still missing
  • No functional data available
BS4 PTEN VCEP applies BS4 when there is a lack of segregation in affected family members. No segregation data is available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available
Still missing
  • No familial segregation data available
BP2 PTEN VCEP applies BP2 when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different P/LP PTEN variants. No such observations have been reported. Details ▾Hide ▴
Evidence considered
  • No observations in trans or cis with pathogenic PTEN variants
BP5 PTEN VCEP applies BP5 when the variant is found in a case with an alternate molecular basis for disease, requiring at least two such cases. No cases with an alternate molecular basis have been identified for this variant. Details ▾Hide ▴
Evidence considered
  • No cases with alternate molecular basis identified
Still missing
  • No clinical cases with alternate molecular diagnosis available
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to the same amino acid change as a previously established pathogenic variant or a different variant at the same nucleotide position as a known pathogenic splicing variant. This is a frameshift deletion, not a missense or splicing variant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 under PTEN VCEP applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, or variants causing protein extension. This is a frameshift (out-of-frame) deletion evaluated under PVS1, not an in-frame deletion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 under PTEN VCEP applies to missense changes at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. This is a frameshift deletion, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 under PTEN VCEP applies specifically to missense variants in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 under PTEN VCEP applies to missense variants with REVEL score > 0.7, or to splicing variants with concordance of SpliceAI and VarSeak. This is a frameshift deletion; REVEL is not applicable (not a single nucleotide variant), and SpliceAI shows no significant splice impact (max delta 0.02). Details ▾Hide ▴
Evidence considered
  • REVEL not applicable (not a single nucleotide variant)
  • SpliceAI max delta score 0.02 (no predicted splice impact)
PP4 VCEPPP4 is marked Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPPP5 is marked Not Applicable by the PTEN VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPBP1 is marked Not Applicable by the PTEN VCEP. This criterion applies to missense variants in genes where a truncating mechanism is primarily causative. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPBP3 is marked Not Applicable by the PTEN VCEP. This criterion applies to in-frame deletions/insertions in repetitive regions. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/ABP4 under PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked Not Applicable by the PTEN VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 under PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. This is a frameshift coding deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a criterion defined in the PTEN VCEP framework (ClinGen PTEN Expert Panel Specifications Version 3.2) or in the standard ACMG/AMP 2015 criteria. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.923del
Protein (HGVS p.)
NP_000305.3:p.(Arg308LeufsTer9)
GRCh38
chr10:87961014 CG>C
GRCh37
chr10:89720771 CG>C
COSMIC
COSV64291945

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-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -77 bp
0.020
SpliceAI acceptor gainat +172 bp
0.000
SpliceAI donor lossat -100 bp
0.000
SpliceAI donor gainat +349 bp
0.000
Pangolin splice lossmagnitude shown
-0.080
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 under PTEN VCEP applies to missense variants with REVEL score > 0.7, or to splicing variants with concordance of SpliceAI and VarSeak. This is a frameshift deletion; REVEL is not applicable (not a single nucleotide variant), and SpliceAI shows no significant splice impact (max delta 0.02). Details ▾Hide ▴
Evidence considered
  • REVEL not applicable (not a single nucleotide variant)
  • SpliceAI max delta score 0.02 (no predicted splice impact)
BP4 N/ABP4 under PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 under PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact. This is a frameshift coding deletion, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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.
    Review article summarizing PTEN's role as a tumor suppressor, its phosphatase activity toward PtdIns-3,4,5-P3, and involvement in sporadic cancers and autosomal dominant hamartoma syndromes. NM_000314.8:c.923del was not identified in this paper.
    Does not name this variant
    PMID 11237521 ↗
  • Essential role for nuclear PTEN in maintaining chromosomal integrity.
    Reports a nuclear function for PTEN in maintaining chromosomal integrity, showing that PTEN inactivation leads to extensive chromosomal aberrations. NM_000314.8:c.923del was not identified in this paper.
    Does not name this variant
    PMID 17218262 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

SpliceAI Lookup Recorded maximum delta 0.020 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-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 = 0.02).

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 previously been reported in somatic cancers (COSMIC; COSV64291945, n = 7 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.