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LYFE SCIENCES
Project: HERA
NM_000314.8:c.367C>G
p.His123Asp  ·  PTEN
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
5

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.

cspec ↗ clinvar ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64294365, n = 3 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueH123
Hotspots ↗