The PTEN c.434T>G (p.Phe145Cys; p.F145C) variant has been observed once in somatic cancers in COSMIC and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.001% and supports PM2 at Supporting strength.2 In the PTEN saturation mutagenesis phosphatase assay, p.Phe145Cys had a cumulative activity score of -0.669, which is above the PTEN PS3_Moderate cutoff of <= -1.11 and below the BS3 threshold of >0, so the current functional evidence does not independently meet PS3 or BS3.3 Computational evidence supports a deleterious protein effect because the REVEL score is 0.861, above the PTEN PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.4
PTEN
Final classification
VUS
PTEN c.434T>G · p.Phe145Cys
PTEN
The PTEN c.434T>G (p.Phe145Cys; p.F145C) variant has been observed once in somatic cancers in COSMIC and has not been reported in ClinVar.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP2PP3
VUS
PTEN c.434T>G
PM2 + PP2 + PP3
→
VUS
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.861. BayesDel score = 0.334659.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV100909311, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links