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PTENc.418_430delLikely pathogenic
Print report
Variant interpretation report

PTEN c.418_430del, p.(Leu140AsnfsTer3)

NM_000314.8:c.418_430del NP_000305.3:p.(Leu140AsnfsTer3) 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

This variant is a frameshift deletion predicted to cause p.(Leu140AsnfsTer3) [p.(L140Nfs*3)]. Under the PTEN-specific PVS1 decision tree, a nonsense or frameshift variant at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 meets PVS1 at very strong strength; c.418_430del is well 5' to this threshold and is consistent with a loss-of-function effect in PTEN.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. This observed allele frequency of 0 is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%), with no subpopulation evidence exceeding the <0.00002 (0.002%) requirement, so PM2_Supporting is met.

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.

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.

Cancer Hotspots

This variant lies 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 · 4 not met · 12 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.418_430del (p.Leu140AsnfsTer3; p.L140Nfs*3) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports PM2 at supporting strength under the PTEN Expert Panel threshold for rarity.

This deletion causes a frameshift with premature termination after codon 140, and under the PTEN-specific PVS1 decision tree the premature stop is 5' to p.D375 (c.1121), supporting a loss-of-function effect.

SpliceAI predicts possible splice impact with a maximum delta score of 0.28, but this alone does not meet the PTEN Expert Panel requirement for concordant computational evidence for PP3 or BP4.

Met · 2

PVS1 Very strongThis variant is a frameshift deletion predicted to cause p.(Leu140AsnfsTer3) [p.(L140Nfs*3)]. Under the PTEN-specific PVS1 decision tree, a nonsense or frameshift variant at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 meets PVS1 at very strong strength; c.418_430del is well 5' to this threshold and is consistent with a loss-of-function effect in PTEN. Details ▾Hide ▴
Rule
PTEN Expert Panel PVS1 decision tree for null variants in NM_000314.8.
Evidence considered
  • NM_000314.8:c.418_430del causes NP_000305.3:p.(Leu140AsnfsTer3) / p.(L140Nfs*3).
  • PTEN loss of function is an established disease mechanism in the PTEN Expert Panel framework.
  • PTEN PVS1 decision tree assigns PVS1 to frameshift variants at or 5' to p.D375 (c.1121).
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. This observed allele frequency of 0 is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%), with no subpopulation evidence exceeding the <0.00002 (0.002%) requirement, so PM2_Supporting is met. Details ▾Hide ▴
Rule
PTEN Expert Panel PM2_Supporting threshold.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • PTEN PM2 is applied at supporting strength when allele frequency is <0.00001 and subpopulation frequency is <0.00002.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PM1 PM1 is specified for variants affecting PTEN catalytic motifs at residues 90-94, 123-130, or 166-168. This frameshift begins at Leu140, which is outside these defined motifs, so PM1 is not met. Details ▾Hide ▴
Rule
PTEN Expert Panel PM1 specification.
Evidence considered
  • PTEN catalytic motifs defined for PM1 are residues 90-94
  • 123-130
  • and 166-168.
  • Variant protein consequence starts at Leu140.
Sources
cspec ↗
PM4 PM4 is specified for in-frame insertions or deletions affecting a catalytic motif or for stop-loss variants causing protein extension. This variant is a frameshift deletion with premature truncation, so PM4 is not met. Details ▾Hide ▴
Rule
PTEN Expert Panel PM4 specification.
Evidence considered
  • PTEN PM4 applies to in-frame indels impacting specified motifs and stop-loss variants.
  • NM_000314.8:c.418_430del is a frameshift deletion.
Sources
cspec ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency of 0 is below the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%). BA1 is not met. Details ▾Hide ▴
Rule
PTEN Expert Panel BA1 threshold.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • PTEN BA1 threshold is >0.00056 (0.056%).
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency of 0 is below both the PTEN Expert Panel BS1 supporting range of 0.0000043 to 0.000043 and strong range of 0.000043 to 0.00056. BS1 is not met. Details ▾Hide ▴
Rule
PTEN Expert Panel BS1 thresholds.
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • PTEN BS1 supporting threshold is 0.0000043 to 0.000043 and strong threshold is 0.000043 to 0.00056.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 12 · no assessment recorded

PS2 No confirmed de novo occurrence in an affected individual was identified, so PS2 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PS2 specification.
Evidence considered
  • PTEN Expert Panel allows PS2 for confirmed de novo observations.
Still missing
  • Documented maternity and paternity confirmation with no family history.
Sources
cspec ↗
PS3 No well-established functional study specific to this deletion was identified. The PTEN Expert Panel phosphatase assay guidance in Mighell et al. applies to missense variants, and no RNA or other assay demonstrating a damaging effect for this variant was identified. Details ▾Hide ▴
Rule
PTEN Expert Panel PS3 specification.
Evidence considered
  • Mighell PTEN assay guidance is indexed for missense variants.
  • No variant-specific PS3-supporting assay result was identified for NM_000314.8:c.418_430del.
Still missing
  • Variant-specific functional or RNA assay data.
Sources
cspec ↗vcep_m_m_c_2
PS4 No proband count, specificity score, or case-control enrichment data were identified for this variant, so PS4 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PS4 specification.
Evidence considered
  • ClinVar contains no submission for this variant.
  • PTEN Expert Panel PS4 requires phenotype-specific proband evidence or increased prevalence in affected individuals.
Still missing
  • Published affected probands with PTEN-specific phenotype data or case-control enrichment evidence.
Sources
cspec ↗clinvar ↗
PM6 No assumed de novo occurrence in a patient with PTEN-related disease and no family history was identified, so PM6 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PM6 specification.
Evidence considered
  • PTEN Expert Panel allows PM6 for assumed de novo observations.
Still missing
  • Documented assumed de novo observation with appropriate phenotype and family history information.
Sources
cspec ↗
PP1 No segregation data were identified for this variant, so PP1 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PP1 specification.
Evidence considered
  • PTEN Expert Panel PP1 requires segregation across informative meioses.
Still missing
  • Segregation data with counted informative meioses.
Sources
cspec ↗
PP3 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, but the PTEN Expert Panel requires concordant splicing prediction evidence for PP3 and this variant is already established as a truncating frameshift under PVS1. In the absence of additional concordant splice evidence, PP3 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PP3 specification.
Evidence considered
  • SpliceAI max delta score = 0.28.
  • PTEN PP3 for splicing variants requires concordant computational evidence.
Still missing
  • Additional concordant splicing prediction or RNA evidence if splice-based assessment is needed.
Sources
cspec ↗spliceai ↗
BS2 No observation of this variant in the homozygous state in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BS2 specification.
Evidence considered
  • PTEN BS2 requires homozygous observation in a healthy or PHTS-unaffected individual.
Still missing
  • Confirmed homozygous observation in an unaffected individual.
Sources
cspec ↗
BS3 No well-established functional study showing no damaging effect for this deletion was identified. The indexed Mighell phosphatase assay guidance applies to missense variants, and no RNA study showing no splicing impact for this variant was identified, so BS3 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BS3 specification.
Evidence considered
  • Mighell assay guidance is indexed for missense variants.
  • No benign functional result for NM_000314.8:c.418_430del was identified.
Still missing
  • Variant-specific benign functional or RNA evidence.
Sources
cspec ↗vcep_m_m_c_2
BS4 No lack-of-segregation data were identified for this variant, so BS4 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BS4 specification.
Evidence considered
  • PTEN BS4 requires documented lack of segregation in affected family members.
Still missing
  • Family data showing lack of segregation in one or more affected families.
Sources
cspec ↗
BP2 No phase data showing this variant in trans with a pathogenic PTEN variant, or repeated cis/phase-unknown observations with different pathogenic PTEN variants, were identified. BP2 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BP2 specification.
Evidence considered
  • PTEN BP2 requires trans or repeated cis/phase-unknown observations with pathogenic PTEN variants.
Still missing
  • Phase information with another pathogenic or likely pathogenic PTEN variant.
Sources
cspec ↗
BP4 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, which is above the benign SpliceAI range of 0 to 0.2 specified by the PTEN Expert Panel, and no concordant benign splicing evidence was identified. BP4 is therefore not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BP4 specification.
Evidence considered
  • SpliceAI max delta score = 0.28.
  • PTEN BP4 for splicing uses benign SpliceAI scores of 0 to 0.2 with concordant prediction evidence.
Still missing
  • Concordant benign splicing predictions if a splice-based benign assessment is needed.
Sources
cspec ↗spliceai ↗
BP5 No alternate highly penetrant molecular explanation with clearly non-overlapping PTEN-related clinical features was identified, so BP5 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BP5 specification.
Evidence considered
  • PTEN BP5 requires an alternate molecular basis for disease with no phenotype overlap.
Still missing
  • Documented alternate molecular diagnosis with non-overlapping phenotype.
Sources
cspec ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change producing the same amino acid substitution or equivalent splice effect. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴
Rule
PTEN Expert Panel PS1 specification.
Evidence considered
  • PS1 is specified for same amino acid change as a previously established pathogenic variant or equivalent splice effect.
Sources
cspec ↗
PM3 N/APM3 is designated not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
Rule
PTEN Expert Panel PM3 applicability.
Evidence considered
  • PTEN Expert Panel marks PM3 as not applicable.
Sources
cspec ↗
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift deletion, so PM5 is not applicable. Details ▾Hide ▴
Rule
PTEN Expert Panel PM5 specification.
Evidence considered
  • PTEN PM5 is specified for missense variants.
Sources
cspec ↗
PP2 N/APP2 is specified for missense variants in PTEN. This variant is a frameshift deletion, so PP2 is not applicable. Details ▾Hide ▴
Rule
PTEN Expert Panel PP2 specification.
Evidence considered
  • PTEN PP2 is a missense-specific criterion.
Sources
cspec ↗
PP4 N/APP4 is designated not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4 rules. Details ▾Hide ▴
Rule
PTEN Expert Panel PP4 applicability.
Evidence considered
  • PTEN Expert Panel marks PP4 as not applicable.
Sources
cspec ↗
PP5 N/APP5 is designated not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
Rule
PTEN Expert Panel PP5 applicability.
Evidence considered
  • PTEN Expert Panel marks PP5 as not applicable.
Sources
cspec ↗
BP1 N/ABP1 is designated not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
Rule
PTEN Expert Panel BP1 applicability.
Evidence considered
  • PTEN Expert Panel marks BP1 as not applicable.
Sources
cspec ↗
BP3 N/ABP3 is designated not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
Rule
PTEN Expert Panel BP3 applicability.
Evidence considered
  • PTEN Expert Panel marks BP3 as not applicable.
Sources
cspec ↗
BP6 N/ABP6 is designated not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
Rule
PTEN Expert Panel BP6 applicability.
Evidence considered
  • PTEN Expert Panel marks BP6 as not applicable.
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is an exonic frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
PTEN Expert Panel BP7 specification.
Evidence considered
  • PTEN BP7 is specified for synonymous or intronic variants at or beyond +7/-21.
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.418_430del
Protein (HGVS p.)
NP_000305.3:p.(Leu140AsnfsTer3)
GRCh38
chr10:87933175 TATTACATCGGGGC>T
GRCh37
chr10:89692932 TATTACATCGGGGC>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

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 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, but the PTEN Expert Panel requires concordant splicing prediction evidence for PP3 and this variant is already established as a truncating frameshift under PVS1. In the absence of additional concordant splice evidence, PP3 is not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel PP3 specification.
Evidence considered
  • SpliceAI max delta score = 0.28.
  • PTEN PP3 for splicing variants requires concordant computational evidence.
Still missing
  • Additional concordant splicing prediction or RNA evidence if splice-based assessment is needed.
Sources
cspec ↗spliceai ↗
BP4 SpliceAI predicts a possible splice effect with a maximum delta score of 0.28, which is above the benign SpliceAI range of 0 to 0.2 specified by the PTEN Expert Panel, and no concordant benign splicing evidence was identified. BP4 is therefore not assessed. Details ▾Hide ▴
Rule
PTEN Expert Panel BP4 specification.
Evidence considered
  • SpliceAI max delta score = 0.28.
  • PTEN BP4 for splicing uses benign SpliceAI scores of 0 to 0.2 with concordant prediction evidence.
Still missing
  • Concordant benign splicing predictions if a splice-based benign assessment is needed.
Sources
cspec ↗spliceai ↗
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is an exonic frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
PTEN Expert Panel BP7 specification.
Evidence considered
  • PTEN BP7 is specified for synonymous or intronic variants at or beyond +7/-21.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.28).

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 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 possible splice impact for this variant (max delta score = 0.28).

Functional

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

Somatic

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

Cancer Hotspots

This variant lies in a statistically significant hotspot.