Final classification

VUS

PS3PM2PP2PP3

PTEN

c.70G>A

p.Asp24Asn

This variant

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.70G>A

GRCh38

chr10:87864539 G>A

GRCh37

chr10:89624296 G>A

PTEN CSPEC explicit final-classification framework from final_classification_framework.json (cspec_ruleset; criteria_combination; Richards et.al., 2015 - Combining rules).

Classification rationale

PS3PM2PP2PP3 VUS

PTEN c.70G>A

The PTEN c.70G>A (p.Asp24Asn) variant has been observed in somatic cancers in COSMIC (COSV64295411; 8 occurrences) and has been reported in ClinVar, where it is classified as pathogenic by three clinical laboratory submissions.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.² Functional testing in the PTEN saturation mutagenesis phosphatase assay showed a high-confidence damaging result for D24N (Cum_score -1.549791026), which supports a deleterious effect on PTEN function.³ Computational evidence supports a deleterious effect for this missense variant based on a REVEL score of 0.753, while SpliceAI predicts no significant splice impact (maximum delta score 0.02).⁴

PS3 + PM2 + PP2 + PP3 → VUS

1 COSMIC COSV64295411ClinVar Variation ID 185200

2 gnomAD v2.1gnomAD v4.1

3 PMID:29706350 ↗PTEN VCEP mmc2.xlsx Table S2

4 REVEL v1.3SpliceAI

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.

Gene diagram · NM_000314.8 · variants mapped to exon structure

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PS3 Moderate review Pathogenic

The PTEN saturation mutagenesis phosphatase assay showed D24N with Cum_score -1.549791026 and High_conf true, which meets the PTEN VCEP threshold for PS3_Moderate (Cum_score <= -1.11).

mmc2.xlsx Table S2: D24N, Cum_score -1.549791026High_conf: true (Pass SE Filter)PTEN CSPEC PS3_Moderate threshold: phosphatase activity score <= -1.11

PMID:29706350 ↗

PM2 Supporting review Pathogenic

The variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTEN PM2_Supporting population criterion.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗

PP2 Supporting review Pathogenic

This is a missense variant in PTEN, and PP2 is retained as an applicable PTEN missense-gene-level supporting criterion in the PTEN specification.

Variant class: missensePTEN CSPEC includes PP2 for missense variants

PP3 Supporting review Pathogenic

The REVEL score is 0.753, exceeding the PTEN missense PP3 threshold of >0.7. SpliceAI shows no significant splice effect, but PP3 for PTEN missense variants is based on REVEL.

REVEL score 0.753PTEN CSPEC PP3 threshold for missense: REVEL > 0.7SpliceAI max delta 0.02

spliceai ↗

Assessed · not applied · 7 not met · 8 not assessed

Pathogenic

PS1 No evidence was identified for a different nucleotide change producing the same PTEN p.Asp24Asn amino acid substitution that has already been established as pathogenic.

PS2 No confirmed de novo data were extracted for this variant.

PS4 The variant is present in ClinVar and has been reported in the literature, but the extracted sources do not provide a PTEN-specific proband specificity score or a case-control enrichment analysis sufficient for PS4 strength assignment.

PM1 PTEN residue Asp24 is outside the PTEN CSPEC-defined catalytic motif residues 90-94, 123-130, and 166-168 required for PM1.

PM5 Different missense changes at PTEN Asp24 are present in Table S3 and classified as pathogenic, including p.Asp24His, p.Asp24Tyr, and p.Asp24Gly; however, PM5 additionally requires the queried missense change to have a BLOSUM62 score equal to or less than the known variant.

PM6 No assumed de novo observations were extracted.

PP1 No segregation data were extracted for this variant.

Benign

BA1 The variant is absent from gnomAD and does not approach the PTEN BA1 threshold.

BS1 The variant is absent from gnomAD and does not meet the PTEN BS1 population frequency thresholds.

BS2 No homozygous observations in healthy or PTEN-hamartoma-tumor-syndrome-unaffected individuals were extracted.

BS3 Available functional evidence shows reduced PTEN function rather than no damaging effect.

BS4 No lack-of-segregation data were extracted.

BP2 No phase data with another pathogenic/likely pathogenic PTEN variant were extracted.

BP4 The REVEL score is 0.753, which is not below the PTEN BP4 missense threshold of <0.5.

BP5 No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was extracted.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV64295411, n = 8 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activi

PMID 29706350 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 Moderate

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

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