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PTENc.844G>TPathogenic
Print report
Variant interpretation report

PTEN c.844G>T, p.(Gly282Ter)

NM_000314.8:c.844G>T NP_000305.3:p.(Gly282Ter) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Nonsense variant at codon 282 (c.844G>T, p.Gly282Ter) in exon 8 of PTEN (NM_000314.8). The stop codon occurs well 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay. Per the PTEN VCEP PVS1 decision tree, a nonsense variant with stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 is assigned PVS1 at Very Strong strength.

PS3Moderate
PS3 · moderate

The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, which is well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. This indicates severely depleted phosphatase activity, confirming a damaging effect on the gene product.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%). No subpopulation exceeds the 0.00002 (0.002%) threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule3 (1 Pathogenic.Very Strong + 1 Pathogenic.Moderate + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PS3 moderate, PM2 supporting; maps to 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
0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

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.

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

This variant has previously been reported in somatic cancers (COSMIC; COSV64292277, n = 1 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 v3.2.0, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 7 not met · 7 not assessed · 9 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

PVS1 (Very Strong): c.844G>T is a nonsense variant producing a premature termination codon at position 282 (p.Gly282Ter), located well 5' to the p.D375 threshold in exon 8 of the biologically-relevant transcript NM_000314.8. Per the PTEN VCEP decision tree, this is predicted to undergo NMD and is assigned PVS1 at Very Strong strength.

PS3 (Moderate): The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay demonstrates a cumulative fitness score of -3.248 for p.Gly282Ter, indicating severely depleted phosphatase activity and meeting the PTEN VCEP PS3_Moderate threshold of <= -1.11.

PM2 (Supporting): The variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), satisfying the PTEN VCEP PM2_Supporting criterion of <0.00001 (0.001%).

PM1 not met: Codon 282 lies outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168) and is not in a statistically significant mutational hotspot.

Combined classification: 1 Very Strong (PVS1) + 1 Moderate (PS3) + 1 Supporting (PM2) meets PTEN VCEP Rule 10 (Likely Pathogenic). Insufficient evidence for Pathogenic: no Strong-level criteria met, and only 1 Supporting criterion (Rule 4 requires >=2 Supporting for Pathogenic with PVS1).

Met · 3

PVS1 Very strongNonsense variant at codon 282 (c.844G>T, p.Gly282Ter) in exon 8 of PTEN (NM_000314.8). The stop codon occurs well 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay. Per the PTEN VCEP PVS1 decision tree, a nonsense variant with stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 is assigned PVS1 at Very Strong strength. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP PVS1 decision tree assigns PVS1 (Very Strong) to nonsense variants with stop codon at or 5' to p.D375 (c.1121) in transcript NM_000314.8
  • Codon 282 is well 5' to the p.D375 (codon 375
  • c.1121) positional threshold
  • Exon 8 is present in the biologically-relevant transcript NM_000314.8
  • Variant is predicted to undergo NMD based on the 50-nucleotide rule (stop >50 nt upstream of last exon-exon junction)
Sources
vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment
PS3 ModerateThe Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, which is well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. This indicates severely depleted phosphatase activity, confirming a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 saturation mutagenesis: G282* (Gly282Ter) Cum_score = -3.248
  • High_conf = True
  • Cum_score <= -1.11 meets PTEN VCEP PS3_Moderate threshold
  • The nonsense variant results in complete loss of the C-terminal region including critical domains
  • consistent with loss of phosphatase function
Sources
vcep_mmc2
PM2 SupportingThis variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%). No subpopulation exceeds the 0.00002 (0.002%) threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: AF = 0.00000% (0/1
  • 609
  • 868 alleles
  • 0 homozygotes)
  • Highest subpopulation AF (African/African American): 0.00000% (0/73
  • 486 alleles)
  • Meets PTEN VCEP PM2_Supporting: allele frequency < 0.00001 (0.001%)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 7 · evaluated, threshold not reached

PS1 No previously established pathogenic variant resulting in the same amino acid change (p.Gly282Ter) was identified in ClinVar or the literature. The ClinVar entry for this variant (VCV004856217) is classified as Uncertain Significance by a single submitter. No other nucleotide change producing p.Gly282Ter has been classified as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV004856217: this variant itself is classified as Uncertain Significance
  • not pathogenic
  • No independent pathogenic or likely pathogenic classification exists for p.Gly282Ter from a different nucleotide change
Sources
clinvar ↗
PM1 Codon 282 is not located within any of the PTEN VCEP-specified catalytic motifs (residues 90-94, 123-130, 166-168 per NP_000305.3). The variant also does not lie in a statistically significant mutational hotspot. Details ▾Hide ▴
Evidence considered
  • PTEN VCEP PM1 specifies catalytic motifs at residues 90-94
  • 123-130
  • 166-168
  • codon 282 is outside these regions
  • Hotspot analysis: residue 282 is not in a statistically significant hotspot
Sources
cspec ↗
BA1 The PTEN VCEP BA1 threshold requires a gnomAD filtering allele frequency > 0.00056 (0.056%). This variant has AF = 0 in gnomAD v4.1 (0/1,609,868 alleles) and is absent from gnomAD v2.1, far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00000% (0/1
  • 609
  • 868 alleles)
  • PTEN VCEP BA1 threshold: AF > 0.00056 (0.056%)
  • not met
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The PTEN VCEP BS1_Strong threshold requires a gnomAD filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%). This variant has AF = 0 in gnomAD v4.1, below the BS1 range. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 0.00000% (0/1
  • 609
  • 868 alleles)
  • PTEN VCEP BS1_Strong range: 0.000043-0.00056
  • AF of 0 does not fall in this range
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No homozygous observations are reported in gnomAD. The variant has 0 homozygotes in gnomAD v4.1. No observation in the homozygous state in a healthy or PHTS-unaffected individual has been identified. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0 homozygotes
  • No homozygous observations in any population database
Sources
gnomad_v4 ↗
BS3 The Mighell et al. 2018 functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, indicating severely depleted phosphatase activity. The PTEN VCEP BS3_Supporting threshold requires phosphatase activity >0 per Mighell et al. 2018, which is not met. No functional evidence supports a benign effect. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018: G282* Cum_score = -3.248 (severely damaging)
  • PTEN VCEP BS3_Supporting requires phosphatase activity >0
  • not met
Sources
vcep_mmc2
BP4 The PTEN VCEP BP4 specifies REVEL score < 0.5 for missense variants, but REVEL is not available for this nonsense variant. SpliceAI delta score is 0.04, indicating no significant splice impact, but this alone is insufficient for BP4 in a nonsense variant. BayesDel score of 0.653 suggests a deleterious effect rather than no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no significant splice impact)
  • BayesDel score = 0.652534 (suggests deleterious)
  • REVEL not available for nonsense variants
  • BP4 missense threshold (REVEL < 0.5) cannot be assessed
Sources
spliceai ↗bayesdel

Not assessed · 7 · no assessment recorded

PS2 No de novo observation data are available. No publication or database entry reports this variant as occurring de novo in a patient with PTEN-hamartoma tumor syndrome and no family history. Details ▾Hide ▴
Still missing
  • No de novo reports identified in ClinVar submissions or literature
PS4 No proband or case-control data are available to calculate a specificity score or compare variant prevalence in affected individuals versus controls. Details ▾Hide ▴
Still missing
  • No patient case data available for specificity scoring
PM6 No de novo observations are reported for this variant. No proband data with confirmed or assumed de novo status and no family history of PTEN-hamartoma tumor syndrome are available. Details ▾Hide ▴
Still missing
  • No de novo reports identified
PP1 No co-segregation data are available. No family studies reporting segregation of c.844G>T with disease in multiple affected family members were identified. Details ▾Hide ▴
Still missing
  • No segregation data available
BS4 No segregation data are available to evaluate lack of segregation in affected family members. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No evidence is available regarding observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase unknown with multiple pathogenic/likely pathogenic PTEN variants. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 No evidence is available regarding an alternate molecular basis for disease in a patient carrying this variant. No case with a confirmed highly penetrant pathogenic variant in another gene has been reported. Details ▾Hide ▴
Still missing
  • No data on alternate molecular diagnoses in carriers
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic. c.844G>T is a nonsense variant producing a premature termination codon (p.Gly282Ter), not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 is specified for missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. c.844G>T is a nonsense variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APer PTEN VCEP, PP3 applies to missense variants (REVEL > 0.7) or splicing variants (concordance of SpliceAI and VarSeak). c.844G>T is a nonsense variant. The deleterious impact of protein truncation is captured by PVS1; applying PP3 would constitute double-counting of the same evidence. Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPThe PTEN VCEP specifies PP4 as Not Applicable; phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPThe PTEN VCEP specifies PP5 as Not Applicable. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPThe PTEN VCEP specifies BP1 as Not Applicable. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPThe PTEN VCEP specifies BP6 as Not Applicable. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. c.844G>T is a nonsense variant resulting in a premature termination codon. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a recognized ACMG/AMP criterion code. The standard ACMG/AMP pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5. No PS5 criterion exists in the framework. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.844G>T
Protein (HGVS p.)
NP_000305.3:p.(Gly282Ter)
GRCh38
chr10:87960936 G>T
GRCh37
chr10:89720693 G>T
ClinVar
4856217
COSMIC
COSV64292277

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 / 1,609,868 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,609,868 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%, 0/1609868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73486 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +1 bp
0.040
SpliceAI acceptor gainat +7 bp
0.000
SpliceAI donor lossat +182 bp
0.000
SpliceAI donor gainat -22 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
0.653

How the predictions were used

BP4 The PTEN VCEP BP4 specifies REVEL score < 0.5 for missense variants, but REVEL is not available for this nonsense variant. SpliceAI delta score is 0.04, indicating no significant splice impact, but this alone is insufficient for BP4 in a nonsense variant. BayesDel score of 0.653 suggests a deleterious effect rather than no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.04 (no significant splice impact)
  • BayesDel score = 0.652534 (suggests deleterious)
  • REVEL not available for nonsense variants
  • BP4 missense threshold (REVEL < 0.5) cannot be assessed
Sources
spliceai ↗bayesdel
PP3 N/APer PTEN VCEP, PP3 applies to missense variants (REVEL > 0.7) or splicing variants (concordance of SpliceAI and VarSeak). c.844G>T is a nonsense variant. The deleterious impact of protein truncation is captured by PVS1; applying PP3 would constitute double-counting of the same evidence. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. c.844G>T is a nonsense variant resulting in a premature termination codon. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.652534.

3 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 discussing PTEN discovery, mutational spectrum in sporadic cancers, and its role as a tumor suppressor via PI3K/AKT pathway regulation. NM_000314.8:c.844G>T (p.Gly282Ter) was not identified in this paper.
    Does not name this variant
    PMID 11237521 ↗
  • Essential role for nuclear PTEN in maintaining chromosomal integrity.
    Research article demonstrating nuclear PTEN function in maintaining chromosomal integrity through centromere association with CENP-C and regulation of Rad51-mediated DNA repair. Reports specific PTEN mutants (C124S, R189X) but NM_000314.8:c.844G>T (p.Gly282Ter) was not identified in this paper.
    Does not name this variant
    PMID 17218262 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    ACMG/AMP standards and guidelines for sequence variant interpretation. Provides the classification framework but does not discuss any specific PTEN variant. NM_000314.8:c.844G>T (p.Gly282Ter) was not identified in this paper.
    Does not name this variant
    PMID 25741868 ↗

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

gnomAD v4.1 0 / 1,609,868 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗
ClinVar 1 Uncertain significance 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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1609868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73486 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.652534.

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; COSV64292277, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.