Starting

Initialising…

PTEN

Final classification

VUS

PTEN c.70G>A · p.Asp24Asn

PTEN

Gene

PTEN

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.70G>A

Consequence

N/A

GRCh38

chr10:87864539 G>A

GRCh37

chr10:89624296 G>A

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

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

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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.

PMID PMID:29706350

PMID PMID:29706350 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

6Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB