The PTEN c.263A>G (p.Tyr88Cys; p.Y88C) variant has been observed in somatic cancers in COSMIC (11 occurrences) and has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the PTEN Expert Panel PM2_Supporting threshold.2 In a published PTEN multiplex phosphatase assay, p.Tyr88Cys had a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11 and supports a damaging effect on PTEN function.3 Computational evidence supports a deleterious effect, with REVEL 0.927 above the PTEN Expert Panel PP3 threshold of 0.7 and BayesDel 0.567202, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.03.4
Final classification
VUS
PS3PM2PP2PP3
PTEN
c.263A>G
p.Tyr88Cys
This variant
The PTEN c.263A>G (p.Tyr88Cys; p.Y88C) variant has been observed in somatic cancers in COSMIC (11 occurrences) 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: PS3 moderate, PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PM2PP2PP3
VUS
PTEN c.263A>G
PS3 + 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 · 4 applied · 16 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
Pathogenic
In a published PTEN multiplex phosphatase assay, p.Tyr88Cys showed a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11. This supports a damaging effect on PTEN function.
Mighell et al. functional assayCum_score -1.228158575High confidence measurement
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2_Supporting threshold of 0.001% and supports rarity in the general population.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP2
supporting
Pathogenic
This is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because benign missense variation is relatively low and missense variants are a recognized disease mechanism. This supports PP2 at supporting strength.
Variant is missensePTEN VCEP includes PP2 as applicable
PP3
supporting
Pathogenic
Computational evidence supports a deleterious effect. REVEL is 0.927, which is above the PTEN Expert Panel PP3 threshold of 0.7 for missense variants; BayesDel is also in a deleterious range at 0.567202. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03, supporting a protein-impact rather than splice-impact interpretation.
REVEL 0.927BayesDel 0.567202SpliceAI max delta 0.03
Assessed · not applied
· 9 not met · 7 not assessed
Pathogenic
PVS1
This missense variant does not fall into the PTEN PVS1 null-variant categories.
PS1
No previously established pathogenic PTEN variant producing the same amino acid change was identified.
PS2
No confirmed de novo observation with maternity and paternity testing was identified, so PS2 cannot be assessed from the available evidence.
PS4
This variant has been observed in somatic cancers, but no germline case-count, specificity-score, or case-control evidence was identified to support PS4 under the PTEN Expert Panel rules.
PM1
p.Tyr88Cys is not within the PTEN catalytic motif residues defined by the Expert Panel for PM1 (residues 90-94, 123-130, and 166-168), and no statistically significant hotspot was identified from the available review.
PM5
No different missense change at PTEN Tyr88 established as pathogenic or likely pathogenic was identified in the available ClinVar review.
PM6
No assumed de novo observation without confirmed parentage was identified, so PM6 cannot be assessed from the available evidence.
PP1
No informative segregation data were identified for this variant, so PP1 cannot be assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BA1 threshold of 0.056%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence.
BS2
No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified.
BS3
Available functional evidence does not show retained PTEN function.
BS4
No family study demonstrating lack of segregation was identified, so BS4 cannot be assessed from the available evidence.
BP2
No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with the number of pathogenic variants required by the PTEN Expert Panel.
BP4
Computational evidence does not support a benign interpretation.
BP5
No alternate highly penetrant molecular explanation with non-overlapping clinical features was identified, so BP5 cannot be assessed from the available evidence.
N/A · 8
PM3 · PM4 · 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 = 0.03). REVEL score = 0.927. BayesDel score = 0.567202.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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; COSV64295989, n = 11 times).
Hotspots
This variant does not lie in a statistically significant 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 29706350
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Sources & reference links