The PTEN c.722T>C (p.Phe241Ser) variant has been observed in somatic cancers in COSMIC (COSV64294827, 5 occurrences) and has not been reported in the current ClinVar record set.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).2 Functional studies support a damaging effect on PTEN, including a Mighell et al. phosphatase assay result of Cum_score -2.399 with High_conf=True, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11; OncoKB also describes the variant as Likely Oncogenic with a likely loss-of-function effect.3 Computational evidence supports a deleterious effect for the missense change because the REVEL score is 0.858, above the PTEN Expert Panel PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.4
Final classification
VUS
PS3PM2PP2PP3
PTEN
c.722T>C
p.Phe241Ser
This variant
The PTEN c.722T>C (p.Phe241Ser) variant has been observed in somatic cancers in COSMIC (COSV64294827, 5 occurrences) and has not been reported in the current ClinVar record set.
PTEN CSPEC/VCEP cspec_ruleset v3.2.0 final-classification framework (Richards et al. 2015 combining rules) from final_classification_framework.json; applied criteria were PS3_Moderate, PM2_Supporting, PP2, and PP3.
Classification rationale
PS3PM2PP2PP3
VUS
PTEN c.722T>C
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 · 15 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
review
Pathogenic
This missense variant showed reduced PTEN function in the Mighell et al. phosphatase assay, with Cum_score -2.399 and High_conf=True; this is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function.
mmc2 Table S2: F241S Cum_score=-2.399434227mmc2 Table S2: High_conf=TrueOncoKB: Likely Oncogenic; biological effect Likely Loss-of-function
PM2
Supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).
gnomAD v2.1: absentgnomAD v4.1: absent
PP2
Supporting
review
Pathogenic
This is a missense variant in PTEN, a gene for which missense variants are a common disease mechanism and benign missense variation is relatively constrained, so PP2 is met.
Variant is missense p.(Phe241Ser)PTEN CSPEC retains PP2 as applicable for missense variants
PP3
Supporting
review
Pathogenic
Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel PP3 threshold of >0.7.
REVEL=0.858
Assessed · not applied
· 7 not met · 8 not assessed
Pathogenic
PS1
No different nucleotide change producing the same PTEN p.(Phe241Ser) amino acid substitution was identified as a previously established pathogenic variant, so PS1 is not met.
PS2
No proven de novo observation with confirmed maternity and paternity in an affected individual and no family history was identified, so PS2 cannot be applied from the available evidence.
PS4
Available evidence does not provide a PTEN phenotype specificity score, a qualifying case-control comparison, or sufficiently detailed germline proband data to apply PS4.
PM1
PTEN p.(Phe241Ser) affects residue 241, which is outside the PTEN catalytic motifs defined for PM1 (residues 90-94, 123-130, and 166-168), so PM1 is not met.
PM5
No different pathogenic or likely pathogenic missense change at PTEN residue Phe241 was identified, so PM5 is not met.
PM6
One curated de novo observation was identified, but the available summary does not document absence of family history or enough independent de novo observations to meet the PTEN Expert Panel PM6 thresholds.
PP1
No segregation data with informative meioses were identified, so PP1 cannot be applied.
Benign
BA1
This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%).
BS1
This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BS1 thresholds of >=0.0000043 and therefore does not support a benign frequency-based interpretation.
BS2
No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 cannot be applied.
BS3
Available functional evidence does not show normal PTEN function.
BS4
No lack-of-segregation data in affected family members were identified, so BS4 cannot be applied.
BP2
No phase data showing this variant in trans with a pathogenic PTEN variant or repeated in cis/phase-unknown observations with pathogenic PTEN variants were identified, so BP2 cannot be applied.
BP4
Computational evidence does not support a benign interpretation for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel BP4 threshold of <0.5, even though SpliceAI predicts no meaningful splice effect with a max delta score of 0.01.
BP5
No evidence was identified that this variant was found in at least two cases with a separate highly penetrant molecular diagnosis and non-overlapping PTEN-related phenotype, so BP5 cannot be applied.
N/A · 9
PVS1 · 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 = 0.01).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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; COSV64294827, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
4papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
A comprehensive functional analysis of PTEN mutations: implications in tumor- an
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Moderate
Functionally distinct groups of inherited PTEN mutations in autism and tumour sy
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Moderate
PMID 29706350
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Moderate
Multi-model functionalization of disease-associated PTEN missense mutations iden
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
Moderate
Sources & reference links