About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.782T>A, p.(Leu261His)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PTPN11 VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS4Strong
PS4 · strong
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PP2Supporting
PP2 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: 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: 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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 6 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 5
PS4 StrongThis 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. Details ▾Hide ▴
Rule
RASopathy VCEP PS4 was applied at strong strength in the expert-panel ClinVar record.
Evidence considered
- ClinVar RASopathy expert-panel comment reports 7 independent affected occurrences
- Supporting literature cited in the expert-panel submission
Still missing
- Independent verification of the underlying case count may still be helpful if a downstream review requires primary case-by-case tabulation.
Sources
PM1 ModerateResidue 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. Details ▾Hide ▴
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
PTPN11 PM2 is applied at supporting strength when the variant is absent from gnomAD.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTPN11 PM2 rule requires absence from controls
Still missing
- An earlier expert-panel ClinVar comment noted a very low-frequency gnomAD observation
- so confirmation of the exact population-database version may be useful if this evidence becomes determinative.
Sources
PP2 SupportingThis 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. Details ▾Hide ▴
Rule
PP2 is used for missense variants in genes with low rates of benign missense variation and where missense is a common disease mechanism.
Evidence considered
- PTPN11 PP2 rule is present in the RASopathy specification
- ClinVar expert-panel submission applied PP2 to this variant
Still missing
- If needed
- gene-level missense-constraint documentation can be rechecked directly against the underlying expert-panel source.
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No independently verified evidence was identified showing the same PTPN11 p.(Leu261His) amino acid change from a different nucleotide substitution. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar exact variant record reviewed
- No alternate nucleotide encoding the same amino acid change was identified in the reviewed materials
Still missing
- A confirmed previously established pathogenic alternate nucleotide change encoding p.(Leu261His) would be needed.
Sources
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. Details ▾Hide ▴
Rule
PS3 requires one or more approved assays meeting the RASopathy VCEP standards.
Evidence considered
- ClinVar expert-panel comment states PS3 not met
- PMID:28074573 reported activating effects for the codon 261/262/265 cluster
- RASopathy VCEP approved functional assay framework reviewed
Still missing
- An approved variant-specific functional assay meeting RASopathy VCEP requirements would be needed to apply PS3.
Sources
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. BayesDel is 0.370262, but this score does not override the VCEP REVEL rule. Details ▾Hide ▴
Rule
For PTPN11 missense variants, PP3 requires REVEL >= 0.7 under the VCEP specification.
Evidence considered
- REVEL 0.558
- SpliceAI max delta 0.00
- BayesDel 0.370262
- PTPN11 PP3 threshold REVEL >= 0.7
Sources
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%. Details ▾Hide ▴
Rule
BA1 requires a filtering allele frequency of at least 0.05% in gnomAD for PTPN11.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold >= 0.05%
Sources
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%. Details ▾Hide ▴
Rule
BS1 requires a filtering allele frequency of at least 0.025% in gnomAD for PTPN11.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 threshold >= 0.025%
Sources
BP4 REVEL is 0.558, which is above the BP4 threshold of 0.3, so benign computational evidence is not met. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied. Details ▾Hide ▴
Rule
For PTPN11 missense variants, BP4 requires REVEL <= 0.3 under the VCEP specification.
Evidence considered
- REVEL 0.558
- SpliceAI max delta 0.00
- BayesDel 0.370262
- PTPN11 BP4 threshold REVEL <= 0.3
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant in the reviewed evidence. Details ▾Hide ▴
Rule
PS2 requires scored de novo evidence under the RASopathy VCEP framework.
Evidence considered
- ClinVar record reviewed without case-level confirmed de novo details
Still missing
- Case-level parentage-confirmed de novo data would be needed to score PS2.
Sources
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. Details ▾Hide ▴
Rule
PM5 requires a previously established pathogenic missense change at the same codon.
Evidence considered
- PTPN11 PM5 rule reviewed
- Submitter comment notes other pathogenic variants affecting this residue
- PMID:28074573 describes a mutation cluster affecting Leu261/Leu262/Arg265
Still missing
- A clearly documented pathogenic or likely pathogenic alternate missense change at the same codon should be confirmed directly before applying PM5.
Sources
PM6 No assumed de novo occurrence lacking full parentage confirmation was clearly documented for this variant in the reviewed evidence. Details ▾Hide ▴
Rule
PM6 requires scored de novo evidence without confirmed parentage under the RASopathy VCEP framework.
Evidence considered
- ClinVar record reviewed without PM6-ready case details
Still missing
- Case-level de novo information without full parentage confirmation would be needed for PM6.
Sources
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. Details ▾Hide ▴
Rule
PP1 strength depends on the number of informative meioses in the RASopathy VCEP framework.
Evidence considered
- Single-submitter ClinVar comment mentions segregation but not meiosis count
Still missing
- Pedigree structure
- phenotype data
- and informative meiosis count are needed to apply PP1.
Sources
BS2 No evidence was identified showing this variant in healthy individuals in a manner sufficient for BS2 scoring. Details ▾Hide ▴
Rule
BS2 requires observations in healthy individuals according to the framework scoring system.
Evidence considered
- No qualifying unaffected-carrier evidence identified
- Variant absent from reviewed gnomAD datasets
Still missing
- Well-phenotyped unaffected carrier data would be needed.
Sources
BS4 No non-segregation evidence was identified for this variant. Details ▾Hide ▴
Rule
BS4 requires informative non-segregation evidence.
Evidence considered
- No contradictory segregation data identified
Still missing
- Family data showing lack of segregation would be needed to apply BS4.
Sources
BP2 No phased co-occurrence data were identified that would support BP2 scoring. Details ▾Hide ▴
Rule
BP2 requires scored co-occurrence evidence under the framework.
Evidence considered
- No qualifying co-occurrence evidence identified
Still missing
- Phased genotype data with an established pathogenic variant would be needed.
Sources
BP5 No alternate molecular explanation or negative-point evidence set was identified that would support BP5 scoring. Details ▾Hide ▴
Rule
BP5 depends on negative-point evidence under the framework.
Evidence considered
- No qualifying BP5 evidence identified
Still missing
- Documented alternate diagnosis evidence would be needed to score BP5.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the reviewed PVS1 assessments indicate that it does not fall into a null-variant category for PVS1 application. Details ▾Hide ▴
Rule
PVS1 is not applied to this missense variant in the reviewed framework.
Evidence considered
- Missense change p.(Leu261His)
- PVS1 variant scaffold states this variant is outside generic null-variant buckets
- PTPN11 RASopathy VCEP framework does not support PVS1 use for this variant type
Sources
PM3 N/APM3 is not applicable because this variant is being evaluated in an autosomal dominant RASopathy framework rather than a recessive disease setting. Details ▾Hide ▴
Rule
PM3 is not used in this framework.
Evidence considered
- PTPN11 RASopathy specification marks PM3 as not applicable
Sources
PM4 N/AThis is a missense substitution and does not cause a protein length change, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 is reserved for protein length changes due to in-frame indels or stop-loss variants.
Evidence considered
- Variant is a missense substitution without in-frame length change or stop-loss
Sources
PP4 N/APP4 is not used in this PTPN11 RASopathy VCEP framework for this review. Details ▾Hide ▴
Rule
PP4 is not applied in this framework.
Evidence considered
- PTPN11 RASopathy specification marks PP4 as not applicable
Sources
BS3 N/ABS3 is not applied in this PTPN11 RASopathy VCEP framework for this review. Details ▾Hide ▴
Rule
BS3 is not used in this framework.
Evidence considered
- PTPN11 RASopathy specification marks BS3 as not applicable
- Approved functional assay framework reviewed
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BP1 N/AThis is a missense variant, whereas the RASopathy-specific BP1 guidance is directed to truncating variants in genes without established loss-of-function disease correlation. Details ▾Hide ▴
Rule
RASopathy BP1 is reserved for specified truncating variants in the relevant gene context.
Evidence considered
- Variant is missense rather than truncating
Sources
BP3 N/ABP3 is not applicable in this PTPN11 RASopathy framework. Details ▾Hide ▴
Rule
BP3 is not used in this framework.
Evidence considered
- PTPN11 RASopathy specification marks BP3 as not applicable
Sources
BP6 N/ABP6 is not applied in this framework. Details ▾Hide ▴
Rule
BP6 is not used in this framework.
Evidence considered
- PTPN11 RASopathy specification marks BP6 as not applicable
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying non-coding variants with no predicted splice impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.782T>A
- Protein (HGVS p.)
- NP_001317366.1:p.(Leu261His)
- GRCh38
- chr12:112472969 T>A
- GRCh37
- chr12:112910773 T>A
Gene diagram
Every interpreted variant in PTPN11, mapped onto the exon structure of NM_001330437.1. Select a row to find it on the plot.
PTPN11NM_001330437.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTPN11
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
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. BayesDel is 0.370262, but this score does not override the VCEP REVEL rule. Details ▾Hide ▴
Rule
For PTPN11 missense variants, PP3 requires REVEL >= 0.7 under the VCEP specification.
Evidence considered
- REVEL 0.558
- SpliceAI max delta 0.00
- BayesDel 0.370262
- PTPN11 PP3 threshold REVEL >= 0.7
Sources
BP4 REVEL is 0.558, which is above the BP4 threshold of 0.3, so benign computational evidence is not met. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied. Details ▾Hide ▴
Rule
For PTPN11 missense variants, BP4 requires REVEL <= 0.3 under the VCEP specification.
Evidence considered
- REVEL 0.558
- SpliceAI max delta 0.00
- BayesDel 0.370262
- PTPN11 BP4 threshold REVEL <= 0.3
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying non-coding variants with no predicted splice impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.558. BayesDel score = 0.370262.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243113
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/575203/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112910773-T-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112472969-T-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.7…
- OncoKB ↗www.oncokb.org/gene/PTPN11/L261H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.782T%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.