Starting

Initialising…

PTEN

Final classification

Likely Pathogenic

PTEN c.367C>G · p.His123Asp

PTEN

The PTEN c.367C>G (p.His123Asp) variant has been observed in somatic cancers (COSMIC COSV64294365, n=3) and has been reported in ClinVar, including a pathogenic expert-panel classification.

Gene

PTEN

Transcript

NM_000314.8

HGVS · transcript:coding

NM_000314.8:c.367C>G

Consequence

N/A

GRCh38

chr10:87933126 C>G

GRCh37

chr10:89692883 C>G

Basis Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule13 (Pathogenic.Moderate >=3) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic. ▾

Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule13 (Pathogenic.Moderate >=3) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

Classification rationale

PS3PM1PM2PM5PP2PP3PP5 Likely Pathogenic

PTEN c.367C>G

The PTEN c.367C>G (p.His123Asp) variant has been observed in somatic cancers (COSMIC COSV64294365, n=3) and has been reported in ClinVar, including a pathogenic expert-panel classification.¹ This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold for population rarity.² In the PTEN saturation mutagenesis phosphatase assay, p.His123Asp showed a high-confidence damaging result with cumulative fitness score -4.3458, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11.³ Computational evidence supports a deleterious effect, with REVEL 0.98 above the PTEN Expert Panel PP3 threshold of >0.7 and BayesDel 0.601229 positive, while SpliceAI max delta 0.01 does not suggest splice disruption.⁴ This variant also affects a PTEN catalytic motif residue and a different missense change at the same codon has been established as pathogenic, supporting PM1 and PM5 under the PTEN specification.⁵

PS3 + PM1 + PM2 + PM5 + PP2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

3 vcep_mmc2cspec ↗

4 revelbayesdelspliceai ↗cspec ↗

5 cspec ↗clinvar ↗

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

PTEN NM_000314.8

Fetching transcript structure from UCSC…

Applied criteria · 7 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 · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

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 Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 428277)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.98. BayesDel score = 0.601229.

SpliceAI ↗

Functional Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64294365, n = 3 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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. 7 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:29706350

PMID PMID:29706350 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

11918710 ↗ PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome. ONCOKB

21828076 ↗ A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. ONCOKB

10555148 ↗ Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. CLINVAR

10772829 ↗ Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may require protein phosphatase activity. CLINVAR

16619501 ↗ Tumour suppressor PTEN regulates cell cycle and protein kinase B/Akt pathway in breast cancer cells. CLINVAR

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR