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
Final classification
VUS
PM2PP2PP3
PTEN
c.434T>G
p.Phe145Cys
This variant
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
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 · 3 applied · 17 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of <0.00001 (0.001%) and consistent with an ultra-rare allele in population databases.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.PTEN PM2 is applied at Supporting strength for alleles <0.00001.
PP2
supporting
Pathogenic
This variant is a missense change in PTEN, a gene for which the PTEN VCEP allows PP2 because benign missense variation is relatively low and missense change is an established disease mechanism.
The variant is missense p.(Phe145Cys).PTEN VCEP specifies PP2 as applicable for missense variants.
PP3
supporting
Pathogenic
Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.861, which is above the PTEN PP3 threshold of >0.7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so the in silico concern is for protein effect rather than splicing.
REVEL score 0.861.PTEN PP3 for missense variants uses REVEL >0.7.SpliceAI max delta score 0.01.
Assessed · not applied
· 8 not met · 9 not assessed
Pathogenic
PS1
No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed.
PS2
No de novo data were identified for this variant, so PS2 was not assessed.
PS3
Functional testing from the PTEN saturation mutagenesis assay showed a cumulative phosphatase activity score of -0.669 for p.Phe145Cys, which is above the PTEN PS3_Moderate threshold of <= -1.11.
PS4
The available evidence does not provide germline proband counts, phenotype specificity scoring, or a case-control analysis showing enrichment in affected individuals, so PS4 was not assessed.
PM1
This missense variant affects residue 145, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168).
PM4
This variant is a missense substitution and does not cause an in-frame protein length change or stop-loss, so PM4 is not met.
PM5
No previously established pathogenic missense variant at residue Phe145 was identified in the available evidence, so PM5 was not assessed.
PM6
No assumed de novo observations were identified for this variant, so PM6 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the PTEN BA1 threshold of >0.00056 (0.056%).
BS1
This variant is absent from gnomAD v2.1 and v4.1 and therefore does not reach the PTEN BS1 thresholds of 0.0000043 to 0.000043 for Supporting or 0.000043 to 0.00056 for Strong evidence.
BS2
No observation of this variant in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous individual was identified, so BS2 is not met.
BS3
Available functional evidence does not show normal PTEN function.
BS4
No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.
BP2
No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/unknown phase in at least three observations with different pathogenic PTEN variants, so BP2 was not assessed.
BP4
Computational evidence does not support a benign protein effect for this missense variant because the REVEL score is 0.861, which is above the PTEN BP4 threshold of <0.5.
BP5
No evidence was identified that this variant was found in a case with a separate highly penetrant molecular diagnosis and a non-overlapping clinical history, so BP5 was not assessed.
N/A · 8
PVS1 · PM3 · 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
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