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
PTPN11
Final classification
VUS
PTPN11 c.127C>T · p.Leu43Phe
PTPN11
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 ↗
Gene diagram
· NM_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 2 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.
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