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PTENc.532T>GUncertain significance
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Variant interpretation report

PTEN c.532T>G, p.(Tyr178Asp)

NM_000314.8:c.532T>G NP_000305.3:p.(Tyr178Asp) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate

Y178D (Tyr178Asp) has a cumulative fitness score of -4.72 in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis phosphatase activity assay, well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. The measurement is flagged as high confidence (High_conf=True). This constitutes well-established in vitro functional evidence of a damaging effect on phosphatase activity.

PM2Supporting
PM2 · supporting

NM_000314.8:c.532T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency < 0.001% (0.00001).

PP2Supporting
PP2 · supporting

PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN hamartoma tumor syndrome. This missense variant (Tyr178Asp) meets the PTEN VCEP PP2 criterion.

PP3Supporting
PP3 · supporting

REVEL score of 0.958 exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants, indicating multiple lines of computational evidence support a deleterious effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.

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
1 reported laboratory submissions

1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; 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; COSV64304856, n = 1 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: 4 met · 15 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.532T>G (p.Tyr178Asp) is a missense variant in PTEN exon 6. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

Functional assessment via saturation mutagenesis phosphatase activity assay (Mighell et al. 2018, PMID: 29706350) demonstrates a cumulative fitness score of -4.72, well below the VCEP PS3_Moderate threshold of <= -1.11, with high-confidence measurement (PS3_Moderate).

Computational predictions support a deleterious effect: REVEL score of 0.958 exceeds the VCEP PP3 threshold of > 0.7 (PP3). PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism (PP2).

This variant has been reported in ClinVar as Uncertain significance by a single submitter (VCV000945254) and in COSMIC as a somatic variant (COSV64304856, n=1). OncoKB classifies it as Likely Oncogenic in the somatic context.

Position 178 is outside the VCEP-defined PM1 catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168). No alternate pathogenic missense at residue 178 was identified for PM5. No de novo, cosegregation, or case-control data are available.

Applying the PTEN VCEP v3.2 combination rules: one moderate criterion (PS3_Moderate) and three supporting criteria (PM2_Supporting, PP2, PP3) are met. No combination rule for Likely Pathogenic is satisfied (Rule 13 requires >=3 moderate; Rule 14 requires 2 moderate + >=2 supporting; Rule 15 requires 1 moderate + >=4 supporting). The variant is classified as Uncertain Significance.

Met · 4

PS3 ModerateY178D (Tyr178Asp) has a cumulative fitness score of -4.72 in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis phosphatase activity assay, well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. The measurement is flagged as high confidence (High_conf=True). This constitutes well-established in vitro functional evidence of a damaging effect on phosphatase activity. Details ▾Hide ▴
Evidence considered
  • Mighell et al. 2018 saturation mutagenesis: Y178D Cum_score = -4.72
  • High_conf = True. Exceeds PS3_Moderate threshold (<= -1.11) per PTEN VCEP v3.2.
Sources
vcep_mmc2cspec ↗
PM2 SupportingNM_000314.8:c.532T>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PTEN VCEP PM2_Supporting threshold of allele frequency < 0.001% (0.00001). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • gnomAD v4.1 (exomes)
  • and gnomAD-Canada v1.0. Allele frequency effectively 0
  • below VCEP PM2 threshold of < 0.001%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP2 SupportingPTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN hamartoma tumor syndrome. This missense variant (Tyr178Asp) meets the PTEN VCEP PP2 criterion. Details ▾Hide ▴
Evidence considered
  • PTEN is a gene with low benign missense variation rate where missense variants are a common disease mechanism per VCEP v3.2.
Sources
cspec ↗
PP3 SupportingREVEL score of 0.958 exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants, indicating multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.958
  • exceeding VCEP PP3 missense threshold of > 0.7. BayesDel score = 0.593 provides additional in silico support.
Sources
revelcspec ↗

Not met · 15 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change (Tyr178Asp) to have been previously established as pathogenic from a different nucleotide change. No evidence of a pathogenic Y178D from an alternate nucleotide was identified in ClinVar or the PTEN VCEP database. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000945254 for c.532T>G (Y178D) is classified as Uncertain significance with a single submitter. No alternate nucleotide producing Y178D with established pathogenicity was identified.
Still missing
  • No established pathogenic Y178D from a different nucleotide substitution.
Sources
clinvar ↗cspec ↗
PS2 No de novo observation data are available for this variant. PS2 requires confirmed or assumed de novo occurrence in a patient with disease and no family history. Details ▾Hide ▴
Evidence considered
  • No de novo data identified for NM_000314.8:c.532T>G.
Still missing
  • No de novo observations in any source.
PS4 PS4 requires proband specificity scores or significantly increased prevalence in affected individuals. No proband data or case-control study data are available for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000945254: single submitter
  • no assertion of pathogenicity
  • no proband count or specificity score available.
Still missing
  • No proband-level phenotype data
  • no case-control study.
Sources
clinvar ↗
PM1 The PTEN VCEP defines PM1 for residues in catalytic motifs: WPD loop (90-94), P-loop (123-130), and TI-loop (166-168). Position 178 (Tyr178) lies 12 residues C-terminal to the TI-loop and is not within any VCEP-defined PM1 domain. CancerHotspots.org identifies this residue as statistically significant, but the VCEP specification is authoritative and does not include residue 178. Details ▾Hide ▴
Evidence considered
  • Position 178 (Tyr178) is outside PTEN VCEP-defined catalytic motifs (90-94
  • 123-130
  • 166-168). CancerHotspots residue significance noted but does not override VCEP specification.
Sources
cspec ↗
PM5 PM5 requires a different missense change at the same residue (Tyr178) with established pathogenic or likely pathogenic classification, with the variant under assessment having an equal or lower BLOSUM62 score. The only other missense at position 178 in the PTEN ClinVar dataset (Table S3) is Y178C (c.533A>G), classified as Uncertain significance. No P/LP missense comparator at residue 178 was identified. Details ▾Hide ▴
Evidence considered
  • Table S3 of mmc2.xlsx lists Y178C (c.533A>G) at same residue
  • classified as Uncertain significance. No P/LP missense comparator at residue 178 identified.
Still missing
  • No P/LP missense comparator at residue 178.
Sources
vcep_mmc2pm5_candidates
PM6 No assumed or confirmed de novo data are available for this variant. PM6 requires de novo observation without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo observations identified in any source.
Still missing
  • No de novo data.
PP1 No cosegregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members with at least 3 meioses. Details ▾Hide ▴
Evidence considered
  • No cosegregation data available.
Still missing
  • No family cosegregation data.
BA1 BA1 requires filtering allele frequency > 0.056% in gnomAD. This variant is absent from gnomAD v2.1 and v4.1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1
  • allele frequency is 0
  • not meeting BA1 threshold of > 0.056%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 BS1 requires filtering allele frequency of 0.00043%-0.056% in gnomAD. This variant is absent from population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • allele frequency is 0
  • not in BS1 range (0.00043%-0.056%).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported for this variant. Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD
  • no homozygous observations in any population database.
Still missing
  • No homozygous or clinical phenotype data for unaffected individuals.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 BS3_Supporting requires phosphatase activity > 0 per Mighell et al. 2018. Y178D has a cumulative fitness score of -4.72, indicating damaging effect, not benign. BS3_Strong does not apply as it is limited to splicing assays for intronic/synonymous variants. Details ▾Hide ▴
Evidence considered
  • Y178D Cum_score = -4.72
  • well below 0. BS3_Supporting threshold (> 0) is not met. Variant demonstrates damaging
  • not benign
  • functional effect.
Sources
vcep_mmc2
BS4 No lack of segregation data are available for this variant. BS4 requires lack of segregation in affected members of one or more families. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation data.
BP2 No evidence of this variant observed in trans with a P/LP PTEN variant or in cis with different P/LP PTEN variants. Details ▾Hide ▴
Evidence considered
  • No phase data or co-occurrence observations available.
Still missing
  • No phase information available.
BP4 BP4 for missense variants requires REVEL score < 0.5 per PTEN VCEP. The REVEL score for this variant is 0.958, well above the BP4 threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.958
  • exceeding BP4 missense threshold of < 0.5. SpliceAI delta = 0.00 but BP4 splicing criteria apply to synonymous/intronic variants only.
Sources
revelcspec ↗
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. BP5 requires at least two such cases per PTEN VCEP specification. Details ▾Hide ▴
Evidence considered
  • No observations of this variant in cases with an alternate molecular diagnosis.
Still missing
  • No data on alternate molecular diagnoses.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice site, CNV) per the PTEN VCEP decision tree. NM_000314.8:c.532T>G is a missense variant (p.Tyr178Asp) and does not qualify. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Tyr178Asp)
  • not a null variant eligible for PVS1 per PTEN VCEP v3.2 decision tree.
Sources
vcep_pvs1_decisiontree_pten
PP4 VCEPPP4 is not applicable per PTEN VCEP v3.2. Phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴
Evidence considered
  • PP4 designated Not Applicable by PTEN VCEP v3.2.
Sources
cspec ↗
PP5 VCEPPP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation, as stated in the PTEN VCEP v3.2. Details ▾Hide ▴
Evidence considered
  • PP5 designated Not Applicable for this VCEP by PTEN EP v3.2.
Sources
cspec ↗
BP1 VCEPBP1 is not applicable to PTEN per the VCEP v3.2 specification. This criterion applies only to genes where primarily truncating variants cause disease, which is not the case for PTEN. Details ▾Hide ▴
Evidence considered
  • BP1 designated Not Applicable for PTEN by VCEP v3.2.
Sources
cspec ↗
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, per PTEN VCEP v3.2. Details ▾Hide ▴
Evidence considered
  • BP6 designated Not Applicable for this VCEP by PTEN EP v3.2.
Sources
cspec ↗
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. NM_000314.8:c.532T>G is a missense variant (p.Tyr178Asp). Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Tyr178Asp)
  • BP7 is restricted to synonymous and intronic variants.
Sources
cspec ↗
PS5 N/APS5 is not defined in the ClinGen PTEN Expert Panel Specifications v3.2. In VCEP mode, criteria not established by the expert panel are not applicable. Details ▾Hide ▴
Evidence considered
  • PS5 absent from PTEN VCEP v3.2 criteria list.
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.532T>G
Protein (HGVS p.)
NP_000305.3:p.(Tyr178Asp)
GRCh38
chr10:87952157 T>G
GRCh37
chr10:89711914 T>G
ClinVar
945254
COSMIC
COSV64304856

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 +5 bp
0.000
SpliceAI acceptor gainat -39 bp
0.000
SpliceAI donor lossat +5 bp
0.000
SpliceAI donor gainat +102 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.958
BayesDel
0.593

How the predictions were used

PP3 SupportingREVEL score of 0.958 exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants, indicating multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.958
  • exceeding VCEP PP3 missense threshold of > 0.7. BayesDel score = 0.593 provides additional in silico support.
Sources
revelcspec ↗
BP4 BP4 for missense variants requires REVEL score < 0.5 per PTEN VCEP. The REVEL score for this variant is 0.958, well above the BP4 threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score = 0.958
  • exceeding BP4 missense threshold of < 0.5. SpliceAI delta = 0.00 but BP4 splicing criteria apply to synonymous/intronic variants only.
Sources
revelcspec ↗
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants. NM_000314.8:c.532T>G is a missense variant (p.Tyr178Asp). Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Tyr178Asp)
  • BP7 is restricted to synonymous and intronic variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.958. BayesDel score = 0.593216.

6 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

  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    Saslow D et al. · 2007
    American Cancer Society guidelines for breast screening with MRI. NM_000314.8:c.532T>G was not identified in this paper.
    Does not name this variant
    PMID 17392385 ↗
  • PTEN Hamartoma Tumor Syndrome.
    Adam MP et al. · 1993
    GeneReviews entry for PTEN Hamartoma Tumor Syndrome. Discusses PTEN-associated conditions at the gene level. NM_000314.8:c.532T>G was not identified as a specific variant in this review.
    Does not name this variant
    PMID 20301661 ↗
  • Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.
    Daly MB et al. · 2014
    NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian. Discusses BRCA1/BRCA2, TP53, and PTEN testing at the gene level. NM_000314.8:c.532T>G was not identified in this paper.
    Does not name this variant
    PMID 25190698 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    PDQ Cancer Genetics overview of breast and gynecologic cancers. NM_000314.8:c.532T>G was not identified in this paper.
    Does not name this variant
    PMID 26389210 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi
    PDQ Cancer Genetics Risk Assessment and Counseling overview. NM_000314.8:c.532T>G was not identified in this paper.
    Does not name this variant
    PMID 26389258 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Describes the Sherloc variant classification framework as a refinement of ACMG-AMP guidelines. NM_000314.8:c.532T>G (p.Tyr178Asp) was not identified in this paper.
    Does not name this variant
    PMID 28492532 ↗

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 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

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 (1 clinical laboratory). (ClinVarID = 945254)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.958. BayesDel score = 0.593216.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64304856, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.