About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.1052G>A, p.(Arg351Gln)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
The PTPN11 VCEP BA1 threshold is gnomAD filtering allele frequency at least 0.05%. In gnomAD v2.1, this variant has grpmax FAF 0.28984% and highest observed population AF 0.34303% in South Asian samples (105/30610), which are above the 0.05% threshold, so BA1 is met.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
Recorded classification: Benign
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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP6 supporting benign; maps to Benign.
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
This variant is present in gnomAD v2.1 (AF= 0.000425539; MAF= 0.04255%, 107/251446 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00343025; MAF= 0.34303%, 105/30610 alleles, homozygotes = 0); grpmax FAF= 0.00289841.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions
5 Benign · 1 Uncertain significance · 1 Likely benign.
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
5 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61012894, n = 5 times).
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 · 7 not met · 10 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.1052G>A (p.Arg351Gln) variant has been observed in somatic cancers in COSMIC and is reported in ClinVar with an expert-panel benign classification.
In population data, this variant is present in gnomAD v2.1 with overall AF 0.04255% (107/251446), South Asian AF 0.34303% (105/30610), and grpmax FAF 0.28984%, which is above the PTPN11 VCEP BA1 threshold of 0.05%; it was not observed in gnomAD v4.1.
Available computational evidence does not meet the PTPN11 VCEP PP3 threshold because REVEL is 0.516, below the required 0.7, while SpliceAI predicts no significant splice impact with a max delta score of 0.00.
No criteria match.
Met · 2
BA1 Stand aloneThe PTPN11 VCEP BA1 threshold is gnomAD filtering allele frequency at least 0.05%. In gnomAD v2.1, this variant has grpmax FAF 0.28984% and highest observed population AF 0.34303% in South Asian samples (105/30610), which are above the 0.05% threshold, so BA1 is met. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >= 0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.0028984100000000006.
- gnomAD v2.1 South Asian AF 0.003430251551780464 (105/30610).
- gnomAD v4.1 absent.
Sources
Not met · 7 · evaluated, threshold not reached
PS1 Available reviewed sources did not identify a previously established pathogenic PTPN11 variant with the same amino acid change, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- No established pathogenic same-amino-acid comparator was identified in the reviewed ClinVar-linked evidence.
Still missing
- A broader same-amino-acid comparator review would be needed to revisit PS1.
Sources
PS4 The available reports and cited publications concern somatic leukemia or JMML settings, and no de-duplicated germline RASopathy case enrichment versus controls was identified. Given the population frequency in gnomAD v2.1, the available evidence does not support PS4. Details ▾Hide ▴
Rule
>=1 point = Supporting; >=3 points = Moderate; >=5 points = Strong.
Evidence considered
- COSMIC reports 5 somatic observations.
- Reviewed papers are leukemia/JMML-focused rather than a germline RASopathy enrichment dataset.
- gnomAD v2.1 shows substantial South Asian frequency.
Still missing
- No de-duplicated germline RASopathy proband count with point-based PS4 scoring was identified.
Sources
PM1 For PTPN11, PM1 is limited to specific listed residues and residue ranges in the N-SH2/PTP interaction interface. Codon 351 is not included in that allowed list, so PM1 is not met. Details ▾Hide ▴
Rule
Applicable only to listed critical residues/residue ranges; not applicable to specific amino acid residues covered by PM5.
Evidence considered
- Codon 351 is outside the VCEP PM1 residue list.
Sources
PM2 PM2 requires absence from gnomAD. This variant is present in gnomAD v2.1 with overall AF 0.04255% (107/251446), South Asian AF 0.34303% (105/30610), and grpmax FAF 0.28984%, so PM2 is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 overall AF 0.0004255386842502963.
- gnomAD v2.1 South Asian AF 0.003430251551780464.
- gnomAD v2.1 grpmax FAF 0.0028984100000000006.
- Absent from gnomAD v4.1.
Sources
PM5 Available reviewed sources did not identify a different pathogenic or likely pathogenic missense change at codon 351 in PTPN11, so the same-residue missense comparator requirement for PM5 is not met. Details ▾Hide ▴
Rule
1 [likely] pathogenic residue change at the same codon.
Evidence considered
- ClinVar review did not provide a qualifying same-residue pathogenic missense comparator.
- The PTPN11 VCEP uses classic same-residue PM5 logic.
Still missing
- A codon-level comparator review beyond the retrieved sources would be needed to revisit PM5.
Sources
PP3 For PTPN11 missense variants, the VCEP PP3 threshold is REVEL at least 0.7. This variant has REVEL 0.516, BayesDel 0.0913187, and SpliceAI max delta score 0.00, so the computational evidence does not meet the PP3 threshold. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.516.
- BayesDel score 0.0913187.
- SpliceAI max delta score 0.00.
Sources
BP4 For PTPN11 missense variants, the VCEP BP4 threshold is REVEL 0.3 or lower. This variant has REVEL 0.516, so BP4 is not met, although SpliceAI predicts no significant splice impact with max delta score 0.00. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3.
Evidence considered
- REVEL score 0.516.
- SpliceAI max delta score 0.00.
- BayesDel score 0.0913187.
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo germline RASopathy observation with maternity and paternity confirmation was identified in the reviewed sources, so PS2 cannot be applied from the currently available evidence. Details ▾Hide ▴
Rule
4 Points / 2 Points / 1 Point under the de novo point-based framework.
Evidence considered
- Reviewed literature leads did not provide confirmed de novo documentation for this variant.
Still missing
- Proband-level inheritance data with confirmed maternity and paternity were not identified.
Sources
PS3 The VCEP allows PS3 only when approved functional assays support a damaging effect. No exact p.(Arg351Gln) result from an approved assay was identified in the reviewed sources, so PS3 cannot be applied from the currently available evidence. Details ▾Hide ▴
Rule
Two or more different approved assays = Moderate; one approved assay = Supporting.
Evidence considered
- Approved assay framework was reviewed.
- Reviewed functional literature leads were not sufficient to confirm an exact-variant approved assay result.
Still missing
- No exact-variant result from a VCEP-approved functional assay was identified.
Sources
PM6 No assumed de novo germline RASopathy observation without maternity and paternity confirmation was identified in the reviewed sources, so PM6 cannot be applied. Details ▾Hide ▴
Rule
0.5 Point / 1 Point / 2 Points under the de novo point-based framework.
Evidence considered
- Reviewed literature leads did not provide qualifying assumed de novo evidence.
Still missing
- No qualifying assumed de novo case was identified.
Sources
PP1 No segregation data with informative meioses were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
>=3 informative meioses = Supporting; >=5 = Moderate; >=7 = Strong.
Evidence considered
- Reviewed literature leads did not provide qualifying segregation counts.
Still missing
- No pedigree data with informative meioses were identified.
Sources
PP2 PP2 requires a gnomAD missense z score greater than 3.09. That gene-level missense constraint value was not identified in the reviewed sources, so PP2 was not assessed. Details ▾Hide ▴
Rule
Missense z score is >3.09 in gnomAD.
Evidence considered
- VCEP PP2 rule requires gnomAD missense z score >3.09.
Still missing
- No reviewed source provided the PTPN11 missense z score needed for PP2.
Sources
BS1 This variant exceeds the BS1 frequency threshold, but BA1 is already met and is the more appropriate stand-alone population criterion, so BS1 was not separately counted. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >= 0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.28984% exceeds the BS1 threshold of 0.025%.
Sources
BS2 Although the variant is present in population databases, no reviewed source documented phenotyped healthy individuals meeting the VCEP BS2 requirements, so BS2 was not applied. Details ▾Hide ▴
Rule
-1 Point / -4 Points under the VCEP point-based framework.
Evidence considered
- Population presence alone was not treated as sufficient for VCEP BS2.
Still missing
- No qualifying healthy-individual evidence with the required phenotypic context was identified.
Sources
BS4 No informative family data showing lack of segregation were identified in the reviewed sources, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Requires only one informative meiosis.
Evidence considered
- Reviewed literature leads did not provide qualifying lack-of-segregation data.
Still missing
- No family-level non-segregation evidence was identified.
Sources
BP2 No evidence was identified showing this variant with a qualifying alternative pathogenic variant in the same gene with the phase and phenotype context required for BP2, so BP2 cannot be applied. Details ▾Hide ▴
BP5 No evidence was identified showing a fully explanatory alternative molecular cause of a RASopathy or a non-RASopathy explanation in the same individual, so BP5 cannot be assessed from the current evidence. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe PTPN11 RASopathy VCEP does not apply PVS1 in this framework, and this variant is a missense change rather than a null variant. Details ▾Hide ▴
Evidence considered
- VCEP marks PVS1 not applicable for this framework.
- Variant-specific PVS1 scaffold does not place this variant in a generic null-variant bucket.
Sources
cspec ↗pvs1_variant_assessment
PM3 VCEPPM3 is not applicable in this dominant RASopathy VCEP framework. Details ▾Hide ▴
PM4 N/AThis is a missense variant and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
- Protein consequence p.(Arg351Gln).
Sources
PP4 VCEPPP4 is not used in this VCEP framework because phenotype specificity is handled through PS4 and related point-based rules. Details ▾Hide ▴
PP5 VCEPPP5 is not used by this VCEP framework. Details ▾Hide ▴
BS3 VCEPBS3 is not used in this VCEP framework. Details ▾Hide ▴
BP1 N/AIn this VCEP framework, BP1 is used for truncating variants in genes where gain of function is the main RASopathy mechanism. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
Use for truncating variants in the specified RASopathy context.
Evidence considered
- Protein consequence p.(Arg351Gln).
Sources
BP3 VCEPThe RASopathy VCEP indicates there are no known benign repetitive regions in these genes for BP3 use, so BP3 is not applicable. Details ▾Hide ▴
BP7 N/ABP7 is for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or certain non-coding variant with no predicted splice impact.
Evidence considered
- Protein consequence p.(Arg351Gln).
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.1052G>A
- Protein (HGVS p.)
- NP_001317366.1:p.(Arg351Gln)
- GRCh38
- chr12:112477975 G>A
- GRCh37
- chr12:112915779 G>A
- ClinVar
- 40541
- COSMIC
- COSV61012894
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
107 / 251,446 alleles
AF 0.000426 · 0 homozygotes · FAF 0.0029
By genetic ancestry
gnomAD v2.1
AF 0.00043 · 107 / 251,446 alleles · 0 hom · FAF 0.0029
| South Asian105 / 30,610 | 0.0034 |
| East Asian1 / 18,394 | 5.4e-05 |
| European (non-Finnish)1 / 113,734 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000425539; MAF= 0.04255%, 107/251446 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00343025; MAF= 0.34303%, 105/30610 alleles, homozygotes = 0); grpmax FAF= 0.00289841.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.516
- BayesDel
- 0.091
How the predictions were used
PP3 For PTPN11 missense variants, the VCEP PP3 threshold is REVEL at least 0.7. This variant has REVEL 0.516, BayesDel 0.0913187, and SpliceAI max delta score 0.00, so the computational evidence does not meet the PP3 threshold. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.516.
- BayesDel score 0.0913187.
- SpliceAI max delta score 0.00.
Sources
BP4 For PTPN11 missense variants, the VCEP BP4 threshold is REVEL 0.3 or lower. This variant has REVEL 0.516, so BP4 is not met, although SpliceAI predicts no significant splice impact with max delta score 0.00. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3.
Evidence considered
- REVEL score 0.516.
- SpliceAI max delta score 0.00.
- BayesDel score 0.0913187.
Sources
BP7 N/ABP7 is for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
A synonymous or certain non-coding variant with no predicted splice impact.
Evidence considered
- Protein consequence p.(Arg351Gln).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0913187.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 15710330 ↗Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations.Mohi MG et al. · 2005No paper-specific finding is recorded.
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PMID 19179468 ↗Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis.Chan G et al. · 2009No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 14644997 ↗Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis.Loh ML et al. · 2004No paper-specific finding is recorded.
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PMID 15385933 ↗PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group.Loh ML et al. · 2004No paper-specific finding is recorded.
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PMID 17972951 ↗Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD.Hou HA et al. · 2008No paper-specific finding is recorded.
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PMID 19047918 ↗Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia.Yoshida N et al. · 2009No paper-specific finding is recorded.
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014No paper-specific finding is recorded.
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PMID 27069254 ↗The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Arber DA et al. · 2016No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
Recorded maximum delta 0.000
Open source ↗
ClinVar
5 Benign · 1 Uncertain significance · 1 Likely benign
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/40541/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112915779-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112477975-G-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/R351Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=219049549
- 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
This variant is present in gnomAD v2.1 (AF= 0.000425539; MAF= 0.04255%, 107/251446 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00343025; MAF= 0.34303%, 105/30610 alleles, homozygotes = 0); grpmax FAF= 0.00289841.
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40541)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0913187.
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 previously been reported in somatic cancers (COSMIC; COSV61012894, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.