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PTENc.405A>GLikely pathogenic
Print report
Variant interpretation report

PTEN c.405A>G, p.(Ile135Met)

NM_000314.8:c.405A>G NP_000305.3:p.(Ile135Met) 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: 5 Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Supporting
PS3 · supporting

Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score (Cum_score) of -0.20 for I135M with High_conf=True, indicating mildly abnormal cellular fitness. This does not meet the PS3_Moderate threshold (Cum_score <= -1.11) but qualifies for PS3_Supporting per the PTEN VCEP specification as an abnormal in vitro cellular assay not reaching PS3_Moderate.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.001% (0.00001) in large population databases.

PM5Moderate
PM5 · moderate

A different missense change at the same residue, I135V (c.403A>G), is classified as Pathogenic in ClinVar (VariationID 142287). BLOSUM62 score for I->M (1) is less than or equal to I->V (3), satisfying the PTEN VCEP BLOSUM62 requirement.

PP2Supporting
PP2 · supporting

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease, meeting the PTEN VCEP PP2_Supporting specification.

PP3Supporting
PP3 · supporting

REVEL score of 0.903 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction.

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 Rule15 (1 Pathogenic.Moderate + Pathogenic.Supporting >=4) with applied criteria: PS3 supporting, PM2 supporting, PM5 moderate, PP2 supporting, PP3 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
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

2 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, conflicting classifications.

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.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV64290722, n = 5 times).

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, with the data and sources behind each one.

26 criteria with recorded statuses: 5 met · 14 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000314.8:c.405A>G (p.Ile135Met) is a missense variant in PTEN exon 5, located in the phosphatase domain adjacent to the catalytic motif (residues 123-130).

This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting per PTEN VCEP).

A different missense change at the same residue, I135V (c.403A>G), is classified as Pathogenic in ClinVar (VariationID 142287), satisfying PM5 at moderate strength with BLOSUM62 score comparison (I->M = 1 <= I->V = 3).

The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -0.20 for I135M (High_conf=True), indicating mildly abnormal cellular fitness. This qualifies for PS3_Supporting per PTEN VCEP as an abnormal in vitro assay not meeting PS3_Moderate (threshold Cum_score <= -1.11).

PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2_Supporting).

REVEL in silico prediction score of 0.903 supports a deleterious effect (PP3_Supporting per PTEN VCEP).

The variant is not within the PTEN VCEP-defined catalytic motif residues (90-94, 123-130, 166-168) despite being in a statistically significant hotspot region; PM1 is not met.

Applying the PTEN VCEP combination rules: one moderate criterion (PM5) and four supporting criteria (PS3_Supporting, PM2_Supporting, PP2, PP3) do not satisfy any Pathogenic or Likely Pathogenic rule. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 5

PS3 SupportingMighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score (Cum_score) of -0.20 for I135M with High_conf=True, indicating mildly abnormal cellular fitness. This does not meet the PS3_Moderate threshold (Cum_score <= -1.11) but qualifies for PS3_Supporting per the PTEN VCEP specification as an abnormal in vitro cellular assay not reaching PS3_Moderate. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 saturation mutagenesis: I135M Cum_score = -0.20 (High_conf=True)
  • mildly abnormal cellular fitness
Sources
vcep_mmc2
PM2 SupportingThis variant is absent from gnomAD v2.1 and v4.1, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency <0.001% (0.00001) in large population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes/genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM5 ModerateA different missense change at the same residue, I135V (c.403A>G), is classified as Pathogenic in ClinVar (VariationID 142287). BLOSUM62 score for I->M (1) is less than or equal to I->V (3), satisfying the PTEN VCEP BLOSUM62 requirement. Details ▾Hide ▴
Evidence considered
  • I135V (c.403A>G) classified as Pathogenic in ClinVar (VariationID 142287)
  • BLOSUM62: I->M = 1 <= I->V = 3
Sources
vcep_mmc2clinvar ↗
PP2 SupportingPTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease, meeting the PTEN VCEP PP2_Supporting specification. Details ▾Hide ▴
Evidence considered
  • PTEN missense constraint: gene has low rate of benign missense variation
  • missense variants are a common disease mechanism in PTEN
Sources
cspec ↗
PP3 SupportingREVEL score of 0.903 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.903 > 0.7
Sources
revelcspec ↗

Not met · 14 · evaluated, threshold not reached

PS1 No other nucleotide change at codon 135 produces the same I135M amino acid substitution that is established as pathogenic. c.405A>G is the only single-nucleotide change that yields Ile135Met. Details ▾Hide ▴

No further detail was recorded.

PS2 No de novo observation data are available for this variant. None of the reviewed publications report a de novo occurrence of NM_000314.8:c.405A>G. Details ▾Hide ▴

No further detail was recorded.

PS4 No proband count or specificity score data are available for this variant to assess enrichment in affected individuals per PTEN VCEP PS4 rules. Details ▾Hide ▴
Still missing
  • No proband-level phenotype data available for specificity scoring
PM1 Residue 135 is not within the PTEN VCEP-defined catalytic motif residues (NP_000305.3 positions 90-94, 123-130, 166-168). Although position 135 lies in the phosphatase domain and is identified as a statistically significant hotspot by cancerhotspots.org, the VCEP specification explicitly defines eligible residues and position 135 is outside these ranges. Details ▾Hide ▴
Evidence considered
  • Residue 135 is just outside the catalytic motif (123-130)
  • hotspot signal present but VCEP definition is strictly residue-based
Sources
cspec ↗
PM6 No de novo observation data are available for this variant. None of the reviewed publications report a de novo occurrence. Details ▾Hide ▴

No further detail was recorded.

PP1 No co-segregation data are available for this variant. No family studies with meiotic counts were identified in the reviewed literature. Details ▾Hide ▴

No further detail was recorded.

BA1 This variant is absent from gnomAD and does not meet the PTEN VCEP BA1 threshold of allele frequency >0.056% (0.00056). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS1 This variant is absent from gnomAD and does not meet the PTEN VCEP BS1 threshold of allele frequency 0.0043% to 0.056%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
Sources
gnomad_v2 ↗gnomad_v4 ↗cspec ↗
BS2 No evidence of homozygous observation in a healthy or PHTS-unaffected individual is available. Details ▾Hide ▴

No further detail was recorded.

BS3 The Mighell et al. 2018 saturation mutagenesis assay reports Cum_score = -0.20 for I135M, which is not >0 and therefore does not qualify for BS3_Supporting per the PTEN VCEP. BS3_Strong is restricted to splicing assays for intronic/synonymous variants, which does not apply to this missense variant. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018: I135M Cum_score = -0.20
  • not >0
Sources
vcep_mmc2cspec ↗
BS4 No segregation data showing lack of segregation in affected family members are available for this variant. Details ▾Hide ▴

No further detail was recorded.

BP2 No evidence of observation in trans with a pathogenic or likely pathogenic PTEN variant, nor three or more observations in cis/phase unknown with different P/LP PTEN variants. Details ▾Hide ▴

No further detail was recorded.

BP4 REVEL score of 0.903 exceeds the PTEN VCEP BP4_Supporting threshold of <0.5 for missense variants. BayesDel score of 0.46 is also not clearly benign. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.903 > 0.5
  • BayesDel = 0.46
Sources
revelbayesdelcspec ↗
BP5 No evidence of this variant occurring in a case with an alternate molecular basis for disease that meets PTEN VCEP criteria. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.405A>G, p.Ile135Met). The PTEN PVS1 decision tree is applicable only to null variants (nonsense, frameshift, canonical splice site, and CNV), not to missense substitutions. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPThe PTEN VCEP specifies that phenotype specificity has been incorporated into the rule specifications for PS4, rendering PP4 not applicable. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPThe PTEN VCEP marks PP5 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPThe PTEN VCEP marks BP1 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPThe PTEN VCEP marks BP6 as Not Applicable. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a recognized criterion in the ACMG/AMP 2015 framework or the PTEN VCEP specifications. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.405A>G
Protein (HGVS p.)
NP_000305.3:p.(Ile135Met)
GRCh38
chr10:87933164 A>G
GRCh37
chr10:89692921 A>G
ClinVar
1737440
COSMIC
COSV64290722

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 v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -151 bp
0.000
SpliceAI acceptor gainat +331 bp
0.000
SpliceAI donor lossat +87 bp
0.000
SpliceAI donor gainat -1 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.903
BayesDel
0.461

How the predictions were used

PP3 SupportingREVEL score of 0.903 exceeds the PTEN VCEP threshold of >0.7 for missense variants, supporting a deleterious computational prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.903 > 0.7
Sources
revelcspec ↗
BP4 REVEL score of 0.903 exceeds the PTEN VCEP BP4_Supporting threshold of <0.5 for missense variants. BayesDel score of 0.46 is also not clearly benign. Details ▾Hide ▴
Evidence considered
  • REVEL = 0.903 > 0.5
  • BayesDel = 0.46
Sources
revelbayesdelcspec ↗
BP7 N/AThis is a missense variant, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.903. BayesDel score = 0.460524.

8 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.
    Marsh DJ et al. · 1999 Aug
    Reports PTEN mutation spectrum in 43 BRR and BRR/CS overlap families. Identifies I135V (c.403A>G) in a familial BRR case (family Ban7) but does not report NM_000314.8:c.405A>G (p.Ile135Met). The I135V finding at the same residue supports PM5 adjudication as a comparator variant.
    → PM5 Does not name this variant
    PMID 10400993 ↗
    Source detail
    Ban7 BRR familial I135V exon 5

    Location Table 1 (PTEN mutations in BRR and BRR/CS overlap patients), family Ban7

Other recorded publications

  • Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.
    Lee JO et al. · 1999
    Reports the X-ray crystal structure of the PTEN tumor suppressor phosphatase domain. NM_000314.8:c.405A>G (p.Ile135Met) was not identified in this structural study.
    Does not name this variant
    PMID 10555148 ↗
  • Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay.
    Han SY et al. · 2000
    Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. NM_000314.8:c.405A>G (p.Ile135Met) was not confirmed in the abstract snippet; full text not available.
    Does not name this variant
    PMID 10866302 ↗
  • High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome.
    Bubien V et al. · 2013
    Reports cancer risk estimates in 146 PHTS patients with 74 distinct germline PTEN mutations. NM_000314.8:c.405A>G (p.Ile135Met) was not among the mutations listed. Genotype-phenotype analyses were limited to mutation type (truncated vs non-truncated) and domain (phosphatase vs C2).
    Does not name this variant
    PMID 23335809 ↗
  • Structure and dimerization of the catalytic domain of the protein phosphatase Cdc14p, a key regulator of mitotic exit in Saccharomyces cerevisiae.
    Kobayashi J et al. · 2017
    Reports the X-ray crystal structure of the budding yeast Cdc14p catalytic domain, a protein phosphatase involved in mitotic exit in Saccharomyces cerevisiae. This paper concerns Cdc14p, not human PTEN, and NM_000314.8:c.405A>G was not mentioned.
    Does not name this variant
    PMID 28758351 ↗
  • Novel mutation of the PTEN gene in an Italian Cowden's disease kindred.
    Scala S et al. · 1998
    Reports mutational analysis of PTEN in one Italian Cowden disease kindred identifying a novel splice site mutation. NM_000314.8:c.405A>G (p.Ile135Met) was not the variant reported.
    Does not name this variant
    PMID 9735393 ↗
  • Molecular alterations associated with cyclin D1 overexpression in endometrial cancer.
    Moreno-Bueno G et al. · 2004
    Investigates molecular alterations associated with cyclin D1 overexpression in endometrial cancer. Reports somatic PTEN mutations in 50% of endometrioid endometrial carcinomas including multiple mutations at codon 130 (R130L, R130Q, R130P, R130G). NM_000314.8:c.405A>G (p.Ile135Met) was not among the mutations detected.
    Does not name this variant
    PMID 15069681 ↗
    Quoted passage
    Codon 130 Missense CGA3CTA Arg130Leu ... Codon 130 Missense CGA3CAA Arg130Gln ... Codon 130 Missense CGA3CCA Arg130Pro ... Codon 130 Missense CGA3GGA Arg130Gly

    Table II (PTEN mutations in endometrioid endometrial carcinomas); reviewed entire full text

  • Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism and a PTEN mutation.
    Boccone L et al. · 2006
    Case report of Bannayan-Riley-Ruvalcaba syndrome with reactive nodular lymphoid hyperplasia and autism. Abstract unavailable; full text not available for review. NM_000314.8:c.405A>G was not confirmed.
    Does not name this variant
    PMID 16894538 ↗

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 0.000 Open source ↗
ClinVar 2 Uncertain significance · 1 Likely pathogenic 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1737440)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.903. BayesDel score = 0.460524.

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 lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64290722, n = 5 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.