About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.1542G>C, p.(Gln514His)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS1Strong
PS1 · strong
ClinVar shows that the same amino acid substitution in PTPN11, p.Gln510His corresponding to this transcript's p.Gln514His, has also been established as pathogenic from a different nucleotide change. SpliceAI predicts no splice effect for this variant (max delta score 0.00), supporting interpretation at the protein level rather than through altered splicing.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTPN11 RASopathy PM2 requirement that the variant be absent from population controls.
PP3Supporting
PP3 · supporting
For missense variants, the PTPN11 RASopathy specification supports PP3 when REVEL is at least 0.7. This variant has REVEL 0.94, which is above the 0.7 threshold; BayesDel is 0.563665, also supporting a deleterious effect, and SpliceAI predicts no significant splice impact with a max delta score of 0.00.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as 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 Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PS1 strong, PM2 supporting, PP3 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.
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: 4 met · 4 not met · 11 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.1542G>C (p.Gln514His) variant has been observed in somatic cancers in COSMIC (8 occurrences) and has been reported in ClinVar as pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls.
ClinVar also documents a different nucleotide change producing the same amino acid substitution, supporting PS1, and in silico results support a deleterious missense effect with REVEL 0.94 above the RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.563665, and no predicted splice impact by SpliceAI (max delta score 0.00).
No criteria match.
Met · 4
PS1 StrongClinVar shows that the same amino acid substitution in PTPN11, p.Gln510His corresponding to this transcript's p.Gln514His, has also been established as pathogenic from a different nucleotide change. SpliceAI predicts no splice effect for this variant (max delta score 0.00), supporting interpretation at the protein level rather than through altered splicing. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- Current variant corresponds to PTPN11 p.Gln510His / p.(Q514H)
- ClinVar also contains a pathogenic alternate nucleotide change producing the same amino acid substitution
- SpliceAI max delta score 0.00
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTPN11 RASopathy PM2 requirement that the variant be absent from population controls. Details ▾Hide ▴
Rule
PM2_Supporting when the variant is absent from gnomAD.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
PP3 SupportingFor missense variants, the PTPN11 RASopathy specification supports PP3 when REVEL is at least 0.7. This variant has REVEL 0.94, which is above the 0.7 threshold; BayesDel is 0.563665, also supporting a deleterious effect, and SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants with REVEL >= 0.7.
Evidence considered
- REVEL 0.94
- BayesDel 0.563665
- SpliceAI max delta 0.00
Sources
Not met · 4 · evaluated, threshold not reached
PM1 The PTPN11 RASopathy specification restricts PM1 to listed critical residues in the N-SH2/PTP interaction interface, and residue 514 is not included in that list. Cancer Hotspots also did not identify this residue as a statistically significant hotspot in the reviewed result. Details ▾Hide ▴
Rule
PM1 applies only to the specified PTPN11 critical residues/domains in the RASopathy specification.
Evidence considered
- PTPN11 PM1 residue list in CSPEC does not include residue 514
- Cancer Hotspots review did not show a significant hotspot row for Q514
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below the BA1 stand-alone benign threshold of 0.05% population frequency. Details ▾Hide ▴
Rule
BA1 requires filtering allele frequency >= 0.05%.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- BA1 threshold 0.05%
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the BS1 benign strong threshold of 0.025% population frequency. Details ▾Hide ▴
Rule
BS1 requires filtering allele frequency >= 0.025%.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- BS1 threshold 0.025%
Sources
BP4 The PTPN11 RASopathy specification supports BP4 for missense variants only when REVEL is 0.3 or lower. This variant has REVEL 0.94, which is above the benign threshold, so BP4 is not met. Details ▾Hide ▴
Rule
BP4 requires REVEL <= 0.3 for missense variants.
Evidence considered
- REVEL 0.94
- BP4 threshold <= 0.3
Sources
cspec ↗revel
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant in the reviewed evidence, so PS2 was not applied. Details ▾Hide ▴
Rule
RASopathy VCEP point-based de novo evidence required.
Evidence considered
- No variant-specific confirmed de novo documentation located
Still missing
- Variant-specific confirmed de novo data with parental testing were not identified.
PS3 RASopathy VCEP-approved functional assay frameworks for PTPN11 were reviewed, but no variant-specific approved functional result for p.(Gln514His) was identified in the reviewed materials. Therefore PS3 was not applied. Details ▾Hide ▴
Rule
Apply only when this specific variant has qualifying abnormal results in approved assays.
Evidence considered
- Approved assay classes exist for PTPN11 (MEK
- ERK
- SHP-2 phosphatase)
- No exact p.(Q514H) result identified
Still missing
- No reviewed assay result for this exact variant was identified from approved functional evidence sources.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:16518851 ↗PMID:21803945 ↗PMID:25741868 ↗PMID:28492532 ↗PMID:31263281 ↗
PS4 This variant has been reported in ClinVar and is classified there as pathogenic by an expert panel, but the reviewed sources did not provide the point-based affected-proband counts required to apply the RASopathy VCEP PS4 rule for this exact variant. PS4 was therefore not applied. Details ▾Hide ▴
Rule
RASopathy VCEP PS4 requires point-based case evidence.
Evidence considered
- ClinVar classification: Pathogenic
- reviewed by expert panel
- No point-based PS4 count available in reviewed files
Still missing
- Exact RASopathy VCEP PS4 points for this variant were not available in the reviewed evidence.
- Independent affected-proband counts for this exact variant were not extracted from the reviewed sources.
Sources
PM5 Other pathogenic missense changes have been reported at the homologous canonical residue, including Gln510Arg and Gln510Glu, which corresponds to this transcript region. However, stronger same-amino-acid evidence supports PS1 for this variant, so PM5 was not applied separately to avoid double counting codon-based evidence. Details ▾Hide ▴
Rule
PM5 not applied separately when stronger PS1 evidence is already used for the same amino acid substitution.
Evidence considered
- Same-codon pathogenic changes reported at canonical residue Gln510
- PS1 already met from same amino acid change with different nucleotide
Sources
PM6 No presumed de novo report without full parental confirmation was identified for this variant in the reviewed evidence, so PM6 was not applied. Details ▾Hide ▴
Rule
RASopathy VCEP point-based de novo evidence required.
Evidence considered
- No variant-specific presumed de novo documentation located
Still missing
- Variant-specific presumed de novo evidence was not identified.
PP1 No segregation data with informative meioses were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
RASopathy VCEP PP1 requires informative meioses.
Evidence considered
- No segregation dataset located
Still missing
- No pedigree or informative meiosis data were identified for this variant.
PP2 The PTPN11 RASopathy framework allows PP2 when the gnomAD missense z score is greater than 3.09, but a gene-level missense z score was not documented in the reviewed case materials. PP2 was therefore not applied. Details ▾Hide ▴
Rule
PP2 requires missense z score >3.09.
Evidence considered
- PP2 threshold in CSPEC reviewed
- No missense z score documented in reviewed case materials
Still missing
- Gene-level missense constraint value was not present in the reviewed files.
Sources
BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals, so BS2 was not applied. Details ▾Hide ▴
Rule
BS2 requires qualifying observations in unaffected individuals.
Evidence considered
- No unaffected-carrier data located
Still missing
- Unaffected-carrier evidence was not identified.
BS4 No nonsegregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
BS4 requires nonsegregation evidence.
Evidence considered
- No nonsegregation data located
Still missing
- No genotype-positive unaffected relative or other nonsegregation evidence was identified.
BP2 No evidence was identified showing this variant in trans with a pathogenic variant for a fully explained phenotype or in a context that would support BP2, so BP2 was not applied. Details ▾Hide ▴
Rule
BP2 requires qualifying point-based phase evidence.
Evidence considered
- No qualifying phase data located
Still missing
- Phase and alternate-cause evidence were not identified.
BP5 No evidence was identified for an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 was not applied. Details ▾Hide ▴
Rule
BP5 requires qualifying negative points for an alternate explanation.
Evidence considered
- No qualifying alternate diagnosis evidence located
Still missing
- No alternate-cause evidence was identified.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the reviewed PVS1 scaffold states that it does not fall into the null-variant categories used for PVS1. The PTPN11 RASopathy specification also lists PVS1 as not applicable for this context. Details ▾Hide ▴
Rule
PVS1 not applied for this missense variant in the PTPN11 RASopathy framework.
Evidence considered
- Missense change p.(Gln514His)/p.(Q514H)
- Generic PVS1 scaffold: not a nonsense
- frameshift
- or canonical +/-1
- 2 splice variant
- PTPN11 CSPEC/VCEP marks PVS1 not applicable
Sources
PM3 N/APM3 is not applicable in the reviewed PTPN11 RASopathy framework for this variant context. Details ▾Hide ▴
Rule
PM3 not applicable in this framework.
Evidence considered
- PTPN11 CSPEC/VCEP lists PM3 as not applicable
Sources
PM4 N/AThis is a missense variant and does not alter protein length. PM4 is intended for in-frame insertions/deletions or stop-loss variants and was not applicable here. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not missense substitutions.
Evidence considered
- Missense substitution p.(Gln514His)
Sources
PP4 N/APP4 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied. Details ▾Hide ▴
Rule
PP4 not applicable in this framework.
Evidence considered
- PTPN11 CSPEC/VCEP lists PP4 as not applicable
Sources
BS3 N/ABS3 is listed as not applicable in the reviewed PTPN11 RASopathy framework for this case and was not applied. Details ▾Hide ▴
Rule
BS3 not applicable in this framework.
Evidence considered
- PTPN11 CSPEC/VCEP lists BS3 as not applicable
Sources
BP1 N/AIn the PTPN11 RASopathy specification, BP1 is used for truncating variants in genes where loss of function is not the established disease mechanism. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies to truncating variants in this framework, not missense variants.
Evidence considered
- Missense substitution p.(Gln514His)
Sources
BP3 N/ABP3 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied. Details ▾Hide ▴
Rule
BP3 not applicable in this framework.
Evidence considered
- PTPN11 CSPEC/VCEP lists BP3 as not applicable
Sources
BP6 N/ABP6 is listed as not applicable in the reviewed PTPN11 RASopathy framework and was not applied. Details ▾Hide ▴
Rule
BP6 not applicable in this framework.
Evidence considered
- PTPN11 CSPEC/VCEP lists BP6 as not applicable
Sources
BP7 N/AThis is a missense variant rather than a synonymous or qualifying intronic/non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying non-canonical splice-region/non-coding variants, not missense variants.
Evidence considered
- Missense substitution p.(Gln514His)
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.1542G>C
- Protein (HGVS p.)
- NP_001317366.1:p.(Gln514His)
- GRCh38
- chr12:112489106 G>C
- GRCh37
- chr12:112926910 G>C
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 missense variants, the PTPN11 RASopathy specification supports PP3 when REVEL is at least 0.7. This variant has REVEL 0.94, which is above the 0.7 threshold; BayesDel is 0.563665, also supporting a deleterious effect, and SpliceAI predicts no significant splice impact with a max delta score of 0.00. Details ▾Hide ▴
Rule
PP3_Supporting for missense variants with REVEL >= 0.7.
Evidence considered
- REVEL 0.94
- BayesDel 0.563665
- SpliceAI max delta 0.00
Sources
BP4 The PTPN11 RASopathy specification supports BP4 for missense variants only when REVEL is 0.3 or lower. This variant has REVEL 0.94, which is above the benign threshold, so BP4 is not met. Details ▾Hide ▴
Rule
BP4 requires REVEL <= 0.3 for missense variants.
Evidence considered
- REVEL 0.94
- BP4 threshold <= 0.3
Sources
cspec ↗revel
BP7 N/AThis is a missense variant rather than a synonymous or qualifying intronic/non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or qualifying non-canonical splice-region/non-coding variants, not missense variants.
Evidence considered
- Missense substitution p.(Gln514His)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.94. BayesDel score = 0.563665.
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/40567/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112926910-G-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112489106-G-C?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/Q514H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=187354876
- 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 (13 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as 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 = 0.94. BayesDel score = 0.563665.
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; COSV61005626, n = 8 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.