About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.127C>T, p.(Leu43Phe)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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: 2 met · 4 not met · 12 not assessed · 10 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.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.
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.
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.
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.
No criteria match.
Met · 2
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP3 SupportingFor 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. Details ▾Hide ▴
Rule
For missense variants: REVEL greater than or equal to 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.924
- SpliceAI max delta score 0.00
- BayesDel 0.57613
Sources
Not met · 4 · evaluated, threshold not reached
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. Available hotspot resources also did not show a statistically significant hotspot at this residue. Details ▾Hide ▴
Rule
Applicable only to specified critical residues and ranges: AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284.
Evidence considered
- PTPN11 PM1 residue list does not include codon 43
- Cancer Hotspots review did not identify a significant hotspot at L43
Sources
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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency greater than or equal to 0.05%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
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. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency greater than or equal to 0.025%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 For missense variants, the PTPN11 RASopathy BP4 rule requires REVEL at or below 0.3. The observed REVEL score is 0.924, which is above that threshold. SpliceAI predicts no splice effect with a maximum delta score of 0.00, but this does not overcome the high missense pathogenicity prediction, so BP4 is not met. Details ▾Hide ▴
Rule
For missense variants: REVEL less than or equal to 0.3.
Evidence considered
- REVEL 0.924
- SpliceAI max delta score 0.00
- BayesDel 0.57613
Sources
Not assessed · 12 · no assessment recorded
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. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- PTPN11 PS1 requires the same amino acid change as a previously established pathogenic variant
- Retrieved ClinVar evidence does not document an alternate nucleotide change causing p.Leu43Phe
Still missing
- Need a verified pathogenic or likely pathogenic variant causing the same amino acid substitution from a different nucleotide change.
Sources
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. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
Supporting with one approved assay; Moderate with two or more different approved assays.
Evidence considered
- RASopathy VCEP functional-study workbook lists approved assay types for PTPN11
- No p.Leu43Phe-specific functional readout was identified in the retrieved materials
- OncoKB did not provide variant-specific reviewed functional evidence
Still missing
- Need variant-specific results from one or more approved functional assays for p.(Leu43Phe).
Sources
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. Details ▾Hide ▴
Rule
RASopathy VCEP point-based prevalence framework.
Evidence considered
- ClinVar cites literature and mixed laboratory classifications
- No PS4 point total was recoverable from the retrieved evidence
Still missing
- Need verified independent proband counts and phenotype specificity.
- Need enough case points to meet the RASopathy PS4 point threshold.
Sources
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. Details ▾Hide ▴
Rule
Moderate for one pathogenic or likely pathogenic residue change at the same codon; Strong for at least two different pathogenic or likely pathogenic residue changes at the same codon observed in at least five probands.
Evidence considered
- PTPN11 PM5 requires established pathogenic variation at the same codon
- Retrieved evidence did not verify a qualifying alternate codon 43 missense change
Still missing
- Need verified pathogenic or likely pathogenic missense variant(s) at the same codon.
Sources
PM6 No de novo report without full parental confirmation was identified for this variant in the retrieved evidence, so PM6 cannot be applied. Details ▾Hide ▴
PP1 No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
Missense z score is greater than 3.09 in gnomAD.
Evidence considered
- PTPN11 PP2 depends on a missense z-score threshold
Still missing
- Need the gnomAD missense constraint z score for PTPN11.
Sources
BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals, so BS2 was not assessed. Details ▾Hide ▴
Rule
RASopathy VCEP point-based benign observation framework.
Evidence considered
- No unaffected-carrier evidence was retrieved
Still missing
- Need observations in unaffected individuals that meet the RASopathy BS2 point framework.
Sources
BS4 No nonsegregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No phase data or alternative molecular diagnosis evidence was identified for this variant, so BP2 was not assessed. Details ▾Hide ▴
Rule
RASopathy VCEP point-based benign framework.
Evidence considered
- No BP2-relevant phase data were retrieved
Still missing
- Need phase information or point-based evidence required by the RASopathy benign framework.
Sources
BP5 No evidence was identified showing that the phenotype is fully explained by an alternate molecular finding, so BP5 was not assessed. Details ▾Hide ▴
Rule
RASopathy VCEP point-based benign framework.
Evidence considered
- No alternate molecular diagnosis data were retrieved
Still missing
- Need benign point-based evidence from an alternate molecular diagnosis framework.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the PTPN11 RASopathy specification marks PVS1 as not applicable. The generic PVS1 assessment also indicates that this variant does not fall into a nonsense, frameshift, or canonical splice-site null-variant category. Details ▾Hide ▴
Rule
Not applicable for this missense variant in the PTPN11 RASopathy specification.
Evidence considered
- PTPN11 VCEP specification lists PVS1 as not applicable
- Generic PVS1 scaffold does not place c.127C>T into a null-variant bucket
Sources
PM3 N/APM3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks PM3 as not applicable
Sources
PM4 N/AThis is a missense substitution rather than an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Variant consequence is missense
Sources
PP4 N/APP4 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks PP4 as not applicable
Sources
PP5 N/APP5 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks PP5 as not applicable
Sources
BS3 N/ABS3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks BS3 as not applicable
Sources
BP1 N/ABP1 in the PTPN11 RASopathy specification is intended for truncating variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply. Details ▾Hide ▴
Rule
Use for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
- Variant consequence is missense
- BP1 guidance in this specification addresses truncating variants
Sources
BP3 N/ABP3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks BP3 as not applicable
Sources
BP6 N/ABP6 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
Rule
Not applicable.
Evidence considered
- PTPN11 RASopathy specification marks BP6 as not applicable
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applies to synonymous, intronic, or non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Variant consequence is missense
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.127C>T
- Protein (HGVS p.)
- NP_001317366.1:p.(Leu43Phe)
- GRCh38
- chr12:112446388 C>T
- GRCh37
- chr12:112884192 C>T
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 SupportingFor 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. Details ▾Hide ▴
Rule
For missense variants: REVEL greater than or equal to 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.924
- SpliceAI max delta score 0.00
- BayesDel 0.57613
Sources
BP4 For missense variants, the PTPN11 RASopathy BP4 rule requires REVEL at or below 0.3. The observed REVEL score is 0.924, which is above that threshold. SpliceAI predicts no splice effect with a maximum delta score of 0.00, but this does not overcome the high missense pathogenicity prediction, so BP4 is not met. Details ▾Hide ▴
Rule
For missense variants: REVEL less than or equal to 0.3.
Evidence considered
- REVEL 0.924
- SpliceAI max delta score 0.00
- BayesDel 0.57613
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applies to synonymous, intronic, or non-coding variants with no predicted splice impact and low conservation.
Evidence considered
- Variant consequence is missense
- SpliceAI max delta score 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.924. BayesDel score = 0.57613.
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/561500/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112884192-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112446388-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/L43F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.127C%3ET
- 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 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
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.