The PTPN11 c.127C>T (p.(Leu43Phe), p.(L43F)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with four submissions classified as uncertain significance and one submission classified as likely pathogenic.1 This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports PM2 at supporting strength under the PTPN11 RASopathy specification.2 Available approved functional-study materials did not provide a variant-specific functional result for p.(Leu43Phe), so PS3 could not be applied from the retrieved evidence.3 Computational evidence supports a damaging missense effect, with REVEL 0.924 above the PP3 threshold of 0.7, BayesDel 0.57613 in a damaging range, and SpliceAI showing no predicted splice effect with a maximum delta score of 0.00.4
Final classification
VUS
PM2PP3
PTPN11
c.127C>T
p.Leu43Phe
This variant
The PTPN11 c.127C>T (p.(Leu43Phe), p.(L43F)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with four submissions classified as uncertain significance and one submission classified as likely pathogenic.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
PTPN11 c.127C>T
PM2 + PP3
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
4
cspec ↗revelbayesdelspliceai ↗
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_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 2 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the PTPN11 RASopathy specification, absence from controls meets PM2 at supporting strength.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP3
supporting
Pathogenic
For this missense variant, REVEL is 0.924, which is above the PTPN11 RASopathy PP3 threshold of 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, supporting a missense rather than splice mechanism, and BayesDel is also in a damaging range at 0.57613. This supports PP3 at supporting strength.
REVEL 0.924SpliceAI max delta score 0.00BayesDel 0.57613
Assessed · not applied
· 4 not met · 12 not assessed
Pathogenic
PS1
No verified evidence was identified showing that this exact amino acid change, p.(Leu43Phe), has previously been established as pathogenic from a different nucleotide change, so PS1 cannot be applied from the retrieved evidence.
PS2
No confirmed de novo occurrence with documented maternity and paternity was identified for this variant, so PS2 cannot be applied from the retrieved evidence.
PS3
Approved functional assay frameworks are available for PTPN11, but no variant-specific result for p.(Leu43Phe) was identified in the retrieved approved functional-study materials, so PS3 cannot be applied from the available evidence.
PS4
This variant has been reported in ClinVar, but the retrieved evidence does not provide a verified count of independent affected probands or a case-control enrichment analysis needed for PS4 under the RASopathy specification.
PM1
The PTPN11 RASopathy specification limits PM1 to specific residues and residue ranges involved in the N-SH2/PTP interface, and codon 43 is not included in that defined PM1 residue set.
PM5
No verified evidence was identified showing a different pathogenic or likely pathogenic missense change at codon 43 that would satisfy the PTPN11 PM5 rule, so PM5 cannot be applied from the retrieved evidence.
PM6
No de novo report without full parental confirmation was identified for this variant in the retrieved evidence, so PM6 cannot be applied.
PP1
No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied.
PP2
The PTPN11 specification allows PP2 when the gene missense z score is greater than 3.09, but no gene-level missense z score was identified in the retrieved case files, so PP2 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 stand-alone benign threshold of 0.05%, so BA1 is not met.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 strong benign threshold of 0.025%, so BS1 is not met.
BS2
No evidence was identified showing this variant in well-phenotyped unaffected individuals, so BS2 was not assessed.
BS4
No nonsegregation data were identified for this variant, so BS4 cannot be applied.
BP2
No phase data or alternative molecular diagnosis evidence was identified for this variant, so BP2 was not assessed.
BP4
For missense variants, the PTPN11 RASopathy BP4 rule requires REVEL at or below 0.3.
BP5
No evidence was identified showing that the phenotype is fully explained by an alternate molecular finding, so BP5 was not assessed.
N/A · 10
PVS1 · PM3 · PM4 · PP4 · PP5 · BS3 · 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.924. BayesDel score = 0.57613.
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. PTPN11, a protein tyrosine phosphatase, is altered in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links