The PTPN11 c.782T>A (p.Leu261His) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen RASopathy expert panel classified it as likely pathogenic and documented 7 independent affected occurrences supporting PS4.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting the PTPN11 RASopathy PM2_Supporting threshold for absence from controls.2 In a published functional study, codon 261/262/265 substitutions increased MAPK pathway signaling, and codon 261 substitutions were described as moderately activating with altered substrate specificity; however, the available assay evidence for this variant did not meet approved RASopathy VCEP PS3 requirements.3 Computational evidence is mixed: REVEL is 0.558, which is below the VCEP PP3 threshold of 0.7 and above the BP4 threshold of 0.3, while SpliceAI predicts no splice impact with a maximum delta score of 0.00.4
Final classification
Likely Pathogenic
PS4PM1PM2PP2PP5
PTPN11
c.782T>A
p.Leu261His
This variant
The PTPN11 c.782T>A (p.Leu261His) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen RASopathy expert panel classified it as likely pathogenic and documented 7 independent affected occurrences supporting PS4.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule11 (1 Pathogenic.Strong + 1 Pathogenic.Moderate) with applied criteria: PS4 strong, PM1 moderate, PM2 supporting, PP2 supporting, PP5 supporting; maps to Likely Pathogenic.
Classification rationale
PS4PM1PM2PP2PP5
Likely Pathogenic
PTPN11 c.782T>A
PS4 + PM1 + PM2 + PP2 + PP5
→
Likely Pathogenic
3
PMID:28074573 ↗clinvar ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelspliceai ↗bayesdelcspec ↗
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 · 5 applied · 14 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PS4
strong
review
Pathogenic
This variant has been reported in 7 independent occurrences in individuals with clinical features of a RASopathy, which supports case enrichment under the expert-panel framework.
ClinVar RASopathy expert-panel comment reports 7 independent affected occurrencesSupporting literature cited in the expert-panel submission
PM1
moderate
review
Pathogenic
Residue Leu261 is explicitly listed in the PTPN11 RASopathy specification as a directly interacting N-SH2/PTP interface residue within a critical and well-established functional region, supporting PM1.
PTPN11 PM1 rule includes amino acid 261 among directly interacting residuesClinVar expert-panel comment states this location is a defined mutational hotspot
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1 in the reviewed population data, meeting the RASopathy VCEP PM2 threshold for absence from controls.
Absent from gnomAD v2.1Absent from gnomAD v4.1PTPN11 PM2 rule requires absence from controls
PP2
supporting
review
Pathogenic
This is a missense variant in PTPN11, a gene/disease setting for which the RASopathy expert panel has identified missense variation as a common pathogenic mechanism and has applied PP2 to this variant.
PTPN11 PP2 rule is present in the RASopathy specificationClinVar expert-panel submission applied PP2 to this variant
Assessed · not applied
· 6 not met · 8 not assessed
Pathogenic
PS1
No independently verified evidence was identified showing the same PTPN11 p.(Leu261His) amino acid change from a different nucleotide substitution.
PS2
No confirmed de novo occurrence with verified maternity and paternity was identified for this variant in the reviewed evidence.
PS3
Published functional work on codon 261 changes showed MAPK pathway activation and altered phosphatase behavior, but the ClinGen RASopathy expert-panel submission states that the assay evidence for this variant did not meet approved PS3 requirements.
PM5
Other disease-associated changes affecting codon 261 have been mentioned in submitter-level evidence, but an independently verified same-codon pathogenic missense comparator suitable for formal PM5 scoring was not fully established from the reviewed sources.
PM6
No assumed de novo occurrence lacking full parentage confirmation was clearly documented for this variant in the reviewed evidence.
PP1
One submitter noted segregation with disease in related individuals, but the reviewed evidence did not provide the number of informative meioses needed for formal PP1 scoring.
PP3
REVEL is 0.558, which is below the PTPN11 RASopathy PP3 threshold of 0.7, and SpliceAI predicts no splice impact with a maximum delta score of 0.00.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the BA1 threshold of at least 0.05%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the BS1 threshold of at least 0.025%.
BS2
No evidence was identified showing this variant in healthy individuals in a manner sufficient for BS2 scoring.
BS4
No non-segregation evidence was identified for this variant.
BP2
No phased co-occurrence data were identified that would support BP2 scoring.
BP4
REVEL is 0.558, which is above the BP4 threshold of 0.3, so benign computational evidence is not met.
BP5
No alternate molecular explanation or negative-point evidence set was identified that would support BP5 scoring.
N/A · 9
PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
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 Pathogenic (1 clinical laboratory) and as Likely pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.558. BayesDel score = 0.370262.
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.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Transcriptional hallmarks of Noonan syndrome and Noonan-like syndrome with loose
Found
Structured finding pending for this record — see source link.
Applied to
→PS4
strong
Functional evaluation of circulating hematopoietic progenitors in Noonan syndrom
Found
Structured finding pending for this record — see source link.
Applied to
→PS4
strong
Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation
Found
Structured finding pending for this record — see source link.
Applied to
→PS4
strong
Sources & reference links