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PTENc.253+5G>ALikely pathogenic
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Variant interpretation report

PTEN c.253+5G>A, p.?

NM_000314.8:c.253+5G>A NP_000305.3:p.? 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

PMID:28677221 reports that NM_000314.8:c.253+5G>A causes exon 4 skipping with predicted protein consequence p.(Ala72Thrfs*5). Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame and is predicted to undergo nonsense-mediated decay in biologically relevant transcript NM_000314.8, and that occurs 5' to p.D375 (c.1121), meets PVS1.

PM2Supporting
PM2 · supporting

The variant is absent from gnomAD v2.1 and has 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of <0.001% overall and <0.002% within any subpopulation.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ACMG/AMP classification using ClinGen PTEN VCEP specifications v3.2.0

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 ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
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 · 8 not met · 12 not assessed · 6 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

An RNA study has shown that NM_000314.8:c.253+5G>A causes exon 4 skipping, resulting in the predicted frameshift transcript consequence p.(Ala72Thrfs*5).

Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame in biologically relevant transcript NM_000314.8 and lies 5′ to p.D375 (c.1121) meets PVS1 at very strong strength; exon 4 skipping to p.(Ala72Thrfs*5) is consistent with this rule.

The variant is absent from gnomAD v2.1 and is observed at 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of 0.001% overall and 0.002% within any subpopulation and supports PM2_Supporting.

With PVS1 and PM2_Supporting under the PTEN VCEP framework, NM_000314.8:c.253+5G>A is classified as likely pathogenic.

Met · 2

PVS1 Very strongPMID:28677221 reports that NM_000314.8:c.253+5G>A causes exon 4 skipping with predicted protein consequence p.(Ala72Thrfs*5). Under the PTEN-specific PVS1 decision tree, a splice alteration that disrupts the reading frame and is predicted to undergo nonsense-mediated decay in biologically relevant transcript NM_000314.8, and that occurs 5' to p.D375 (c.1121), meets PVS1. Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree.
Evidence considered
  • RNA study: exon 4 skipping
  • Predicted frameshift: p.(Ala72Thrfs*5)
  • PTEN PVS1 decision tree threshold at p.D375/c.1121
Sources
PMID:28677221 ↗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 gnomAD v2.1 and has 0/1,448,024 alleles in gnomAD v4.1, with 0/33,128 alleles in the highest observed subpopulation, which is below the PTEN PM2 thresholds of <0.001% overall and <0.002% within any subpopulation. Details ▾Hide ▴
Rule
Absent in population at <0.001% overall and <0.002% in any subpopulation.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AF 0.0
  • gnomAD v4.1 AFR AF 0.0
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not met · 8 · evaluated, threshold not reached

PM1 This is an intronic splice-region variant, not a missense change within PTEN catalytic motif residues 90-94, 123-130, or 166-168. Details ▾Hide ▴
Rule
Located in catalytic motifs 90-94, 123-130, 166-168
Evidence considered
  • Variant location c.253+5
Sources
cspec ↗
PM4 This variant does not create an in-frame protein length change or stop-loss event. Details ▾Hide ▴
Rule
Protein length changes due to in-frame indels or stop-loss variants
Evidence considered
  • Intronic splice variant
PM5 This is not a missense variant at a residue with a different established pathogenic missense change. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different pathogenic missense change has been seen
Evidence considered
  • Intronic splice variant
PP2 PP2 is a missense-specific rule and does not apply to this intronic splice-region variant. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense rate and common missense disease mechanism
Evidence considered
  • Variant class is intronic/splice-region
Sources
cspec ↗
BA1 The gnomAD v4.1 allele frequency is 0.0, which is well below the PTEN BA1 threshold of >0.056%. Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >0.056%
Evidence considered
  • gnomAD v4.1 total AF 0.0
Sources
gnomad_v4 ↗cspec ↗
BS1 The gnomAD v4.1 allele frequency is 0.0, which is below both the PTEN BS1 supporting range of 0.00043%-0.0043% and the strong range of 0.0043%-0.056%. Details ▾Hide ▴
Rule
BS1 supporting 0.00043%-0.0043%; BS1 strong 0.0043%-0.056%
Evidence considered
  • gnomAD v4.1 total AF 0.0
Sources
gnomad_v4 ↗cspec ↗
BP4 SpliceAI predicts possible splice impact with a maximum delta score of 0.81, which is above the PTEN benign SpliceAI range of 0-0.2 required for BP4, and no concordant benign VarSeak result was provided. Details ▾Hide ▴
Rule
For splicing variants, benign evidence requires SpliceAI 0-0.2 and concordant VarSeak benign prediction
Evidence considered
  • SpliceAI max delta score 0.81
Still missing
  • VarSeak result
Sources
spliceai ↗cspec ↗
BP7 The variant is at +5, which is inside the PTEN BP7 positional requirement of at or beyond +7/-21, and SpliceAI predicts splice impact rather than no impact. Details ▾Hide ▴
Rule
Intronic variant must be at or beyond +7/-21 with algorithms predicting no splice impact
Evidence considered
  • Position c.253+5
  • SpliceAI max delta score 0.81
Sources
spliceai ↗cspec ↗

Not assessed · 12 · no assessment recorded

PS1 No same-nucleotide pathogenic splice comparator with equal or greater predicted impact was documented in the reviewed workspace materials. Details ▾Hide ▴
Still missing
  • Variant-specific same-nucleotide pathogenic comparator evidence
PS2 No confirmed de novo data were provided. Details ▾Hide ▴
Still missing
  • Parental testing and phenotype-specific de novo documentation
PS3 An RNA study documents abnormal splicing, but this evidence was used to support PVS1 via the PTEN splice/null decision framework rather than being double-counted separately as PS3. Details ▾Hide ▴
Rule
RNA, mini-gene, or other assay shows impact on splicing
Evidence considered
  • RNA assay showing exon 4 skipping
Sources
PMID:28677221 ↗vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PS4 The reviewed materials did not provide PTEN phenotype specificity scoring or a case-control enrichment dataset sufficient for PS4. Details ▾Hide ▴
Still missing
  • PTEN-specific proband specificity scores or case-control data
PM6 No assumed de novo evidence was provided. Details ▾Hide ▴
Still missing
  • Parental studies or assumed de novo clinical documentation
PP1 No segregation data were provided. Details ▾Hide ▴
Still missing
  • Family segregation data with counted meioses
PP3 SpliceAI shows a maximum delta score of 0.81, consistent with possible splice impact, but the PTEN VCEP rule for splicing variants requires concordance between SpliceAI and VarSeak, and no VarSeak result was available in the reviewed materials. Details ▾Hide ▴
Rule
Splicing variants require concordance of SpliceAI and VarSeak
Evidence considered
  • SpliceAI max delta score 0.81
Still missing
  • VarSeak splicing prediction
Sources
spliceai ↗cspec ↗
BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were provided. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual
Evidence considered
  • gnomAD v4.1 homozygotes = 0
Still missing
  • Documented homozygous unaffected observations
Sources
gnomad_v4 ↗cspec ↗
BS3 No functional study demonstrating no damaging effect on splicing or PTEN function was provided. Details ▾Hide ▴
Still missing
  • Benign functional assay data
BS4 No lack-of-segregation evidence was provided. Details ▾Hide ▴
Still missing
  • Family data showing lack of segregation
BP2 No trans, cis, or phase-unknown observations with pathogenic PTEN variants were provided. Details ▾Hide ▴
Still missing
  • Phase data with pathogenic/likely pathogenic PTEN variants
BP5 No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was provided. Details ▾Hide ▴
Still missing
  • Alternate molecular diagnosis and phenotype overlap assessment
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable for the PTEN VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
PP4 N/APP4 is not applicable for the PTEN VCEP framework because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
Sources
cspec ↗
PP5 N/APP5 is not applicable for the PTEN VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
BP1 N/ABP1 is not applicable for the PTEN VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
BP3 N/ABP3 is not applicable for the PTEN VCEP framework. Details ▾Hide ▴
Sources
cspec ↗
BP6 N/ABP6 is not applicable for the PTEN VCEP framework. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.253+5G>A
Protein (HGVS p.)
NP_000305.3:p.?
GRCh38
chr10:87931094 G>A
GRCh37
chr10:89690851 G>A

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 0 / 1,448,024 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,448,024 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1448024 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/33128 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SpliceAI predicts possible splice impact with a maximum delta score of 0.81, which is above the PTEN benign SpliceAI range of 0-0.2 required for BP4, and no concordant benign VarSeak result was provided. Details ▾Hide ▴
Rule
For splicing variants, benign evidence requires SpliceAI 0-0.2 and concordant VarSeak benign prediction
Evidence considered
  • SpliceAI max delta score 0.81
Still missing
  • VarSeak result
Sources
spliceai ↗cspec ↗
BP7 The variant is at +5, which is inside the PTEN BP7 positional requirement of at or beyond +7/-21, and SpliceAI predicts splice impact rather than no impact. Details ▾Hide ▴
Rule
Intronic variant must be at or beyond +7/-21 with algorithms predicting no splice impact
Evidence considered
  • Position c.253+5
  • SpliceAI max delta score 0.81
Sources
spliceai ↗cspec ↗
PP3 SpliceAI shows a maximum delta score of 0.81, consistent with possible splice impact, but the PTEN VCEP rule for splicing variants requires concordance between SpliceAI and VarSeak, and no VarSeak result was available in the reviewed materials. Details ▾Hide ▴
Rule
Splicing variants require concordance of SpliceAI and VarSeak
Evidence considered
  • SpliceAI max delta score 0.81
Still missing
  • VarSeak splicing prediction
Sources
spliceai ↗cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.81).

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 0 / 1,448,024 recorded alleles 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
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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1448024 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/33128 alleles, homozygotes = 0).

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 = 0.81).

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV64300202, n = 2 times).