Classification rationale

PS3PM2PP2PP3 VUS

PTEN c.256G>C

PTEN final classification was assigned using the explicit CSPEC/VCEP criteria-combination framework rather than generic ACMG/AMP combination rules.¹ The applicable pathogenic evidence consists of PS3_Moderate, PM2_Supporting, PP2, and PP3. This combination provides 1 Moderate and 3 Supporting pathogenic criteria, which does not match a defined PTEN rule for Likely Pathogenic or Pathogenic.² No benign standalone, strong, or supporting rule combination is satisfied, so the variant remains of uncertain significance.³

PS3 + PM2 + PP2 + PP3 → VUS

1 final_classification_framework

2 final_classification_framework

3 final_classification_framework

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 EP specifies PS3_Moderate for Mighell et al. 2018 phosphatase activity score <= -1.11. In local mmc2.xlsx Table S2, A86P / Ala86Pro has Cum_score -2.188961661 with High_conf = True, satisfying PS3_Moderate.

Local PTEN functional file mmc2.xlsx Table S2 contains row A86P / Ala86Pro.Observed values: Cum_score = -2.188961661; High_conf = True.PTEN index guidance states PS3_Moderate applies when Cum_score <= -1.11.

PM2 Supporting review Pathogenic

PTEN EP downgrades PM2 to Supporting for variants absent or extremely rare in large population datasets. This variant is absent from both gnomAD v2.1 and gnomAD v4.1 in the workspace, satisfying PM2_Supporting.

gnomAD v2.1: absent.gnomAD v4.1: absent.

PP2 Supporting review Pathogenic

PTEN EP retains PP2 for missense variants in PTEN because missense variation is a common disease mechanism in a gene with low benign missense variation. This variant is a missense substitution, p.(Ala86Pro), so PP2 is met at Supporting strength.

Variant consequence is missense p.(Ala86Pro).PTEN EP explicitly lists PP2 as applicable for missense variation in PTEN.

PP3 Supporting review Pathogenic

For PTEN missense variants, PP3 applies when REVEL > 0.7. The workspace reports REVEL 0.945 for this variant, satisfying PP3.

REVEL score = 0.945.PTEN EP PP3 missense threshold is REVEL > 0.7.

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PS1 PTEN EP PS1 requires the same amino acid change as a previously established pathogenic variant.

PS2 No proband-level de novo evidence, parental testing, or family history information is present in the workspace.

PS4 PTEN EP PS4 requires germline proband enrichment or phenotype-specific proband scoring.

PM1 PTEN EP PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168 (NP_000305.3).

PM5 PTEN EP PM5 requires a different pathogenic/likely pathogenic missense change at the same residue with appropriate BLOSUM62 comparison.

PM6 No assumed de novo case information is present in the workspace.

PP1 No segregation data or meiosis counts are present in the workspace.

Benign

BA1 PTEN EP BA1 requires filtering allele frequency >0.00056.

BS1 PTEN EP BS1 requires allele frequency within benign threshold ranges.

BS2 PTEN EP BS2 requires homozygous observation(s) in healthy/PHTS-unaffected individuals.

BS3 PTEN EP BS3_Supporting for missense variants requires phosphatase activity >0 in Mighell et al.

BS4 No family-based lack-of-segregation evidence is present in the workspace.

BP2 No phasing data or observations with other pathogenic PTEN variants are present in the workspace.

BP4 For PTEN missense variants, BP4 requires REVEL <0.5.

BP5 No alternate molecular diagnosis or phenotype-overlap analysis is present in the workspace.

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV64309575, n = 1 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.

PMID 29706350

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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