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
PTPN11
Final classification
Likely Pathogenic
PTPN11 c.782T>A · p.Leu261His
PTPN11
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 ↗
Gene diagram
· NM_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 5 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 · 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.
PMID PMID:22253195
Found
Structured finding pending for this record — see source link.
Applied to
→PS4 supports · met
PMID PMID:23756559
Found
Structured finding pending for this record — see source link.
Applied to
→PS4 supports · met
PMID PMID:28074573
Found
Structured finding pending for this record — see source link.
Applied to
→PS4 supports · met
Sources & reference links