About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.209A>G, p.(Lys70Arg)
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
PM1Moderate
PM1 · moderate
Lys70 lies within the PTPN11 N-SH2/PTP interaction interface, and the RASopathy specification explicitly lists residues 69-77 as a critical functional region for PM1 use.
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: 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: PM1 moderate, PP5 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
2 / 1,613,656 alleles
gnomAD v4.1: 2 / 1,613,656 alleles. Recorded AF 1.23942e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
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: 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.209A>G (p.Lys70Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel and was also reported in a patient with Noonan syndrome in a published cohort.
This variant was absent from gnomAD v2.1 and is present only 2 times among 1613656 alleles in gnomAD v4.1 (AF 1.23942e-06; 0.00012%), which is far below the BS1 threshold of 0.025% and the BA1 threshold of 0.05%.
The affected Lys70 residue falls within the PTPN11 critical N-SH2/PTP interaction region explicitly designated by the RASopathy specification for PM1.
Available computational evidence does not meet PP3 or BP4 thresholds because REVEL is 0.668, BayesDel is 0.00798395, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 2
PM1 ModerateLys70 lies within the PTPN11 N-SH2/PTP interaction interface, and the RASopathy specification explicitly lists residues 69-77 as a critical functional region for PM1 use. Details ▾Hide ▴
Rule
PM1 applies to specified critical functional residues, including AA 69-77.
Evidence considered
- PTPN11 PM1 residue list includes AA 69-77
- Variant affects Lys70
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the reviewed ClinVar evidence for Lys70Arg. Details ▾Hide ▴
PM2 PM2_Supporting requires absence from gnomAD, but this variant is present in gnomAD v4.1 at 2/1613656 alleles (AF 1.23942e-06; 0.00012%), even though it was absent from gnomAD v2.1. Details ▾Hide ▴
Rule
PM2_Supporting requires the variant to be absent from controls in gnomAD.
Evidence considered
- Absent from gnomAD v2.1
- Present in gnomAD v4.1 at very low frequency
Sources
PM5 No different pathogenic missense change at codon 70 was identified in the reviewed ClinVar evidence, so the same-codon requirement for PM5 was not met. Details ▾Hide ▴
PP3 PP3 requires REVEL at or above 0.7 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and the available BayesDel score of 0.00798395 does not overcome the unmet REVEL threshold in this framework. Details ▾Hide ▴
Rule
PP3 for missense variants requires REVEL >= 0.7; splicing impact must match disease mechanism when relevant.
Evidence considered
- REVEL 0.668
- BayesDel 0.00798395
- SpliceAI max delta 0.00
Sources
BA1 BA1 requires a gnomAD filtering allele frequency of at least 0.05%, but the observed gnomAD v4.1 allele frequency is 1.23942e-06 (0.00012%), which is far below this threshold. Details ▾Hide ▴
Rule
BA1 requires filtering allele frequency >= 0.05%.
Evidence considered
- gnomAD v4.1 total AF 1.23942e-06
Sources
BS1 BS1 requires a gnomAD filtering allele frequency of at least 0.025%, but the observed gnomAD v4.1 allele frequency is 1.23942e-06 (0.00012%), which is well below this threshold. Details ▾Hide ▴
Rule
BS1 requires filtering allele frequency >= 0.025%.
Evidence considered
- gnomAD v4.1 total AF 1.23942e-06
Sources
BP4 BP4 requires REVEL at or below 0.3 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel score of 0.00798395 does not change the unmet REVEL threshold in this framework. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL <= 0.3.
Evidence considered
- REVEL 0.668
- BayesDel 0.00798395
- SpliceAI max delta 0.00
Sources
Not assessed · 10 · no assessment recorded
PS2 One published Noonan syndrome cohort reported this variant in a sporadic case and stated that identified mutations were de novo, but the available evidence does not provide enough verified parentage and phenotype-specific scoring detail here to assign PS2 confidently. Details ▾Hide ▴
Rule
PS2 strength is assigned by de novo point totals in the RASopathy specification.
Evidence considered
- Published cohort included p.(K70R) in patient 7
- Paper states identified mutations were de novo
Still missing
- Independent de novo point calculation under the RASopathy specification was not available.
- Parentage confirmation details were not directly verified from the reviewed evidence.
Sources
PS3 Approved functional assay classes for PTPN11 are listed by the RASopathy VCEP, but no directly verified variant-specific functional result for p.(Lys70Arg) was identified in the reviewed evidence, so PS3 cannot be assigned at this stage. Details ▾Hide ▴
Rule
PS3 requires one or more approved variant-specific assays under the RASopathy specification.
Evidence considered
- Approved PTPN11 assay classes include MEK activation
- ERK activation
- and SHP-2 phosphatase activity
Still missing
- Direct variant-specific functional assay data for p.(Lys70Arg).
- Underlying primary functional study details tied specifically to this variant.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
PS4 This variant has been reported in ClinVar and in at least one published Noonan syndrome cohort, but the number of unrelated affected probands and the RASopathy PS4 point total could not be verified from the available evidence. Details ▾Hide ▴
Rule
PS4 strength is assigned by point totals under the RASopathy specification.
Evidence considered
- ClinVar expert panel classification
- One published Noonan syndrome case report/cohort entry
Still missing
- Unrelated proband count for this exact variant.
- Verified PS4 point total under the RASopathy specification.
- Confirmation that observations are independent and not duplicated across sources.
Sources
PM6 A published Noonan syndrome cohort reported this variant in a sporadic case and stated that identified mutations were de novo, but the available evidence does not provide enough detail on parentage confirmation and scoring to assign PM6 confidently. Details ▾Hide ▴
Rule
PM6 strength is assigned by de novo point totals when PS2 requirements are not fully met.
Evidence considered
- Published cohort included p.(K70R) and described mutations as de novo
Still missing
- Direct verification of assumed versus confirmed de novo status.
- Independent PM6 point total under the RASopathy specification.
Sources
PP1 No informative segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Rule
PP1 requires informative cosegregation data.
Evidence considered
- No segregation evidence identified
Still missing
- Pedigree-level cosegregation data.
- Informative meiosis count under the RASopathy specification.
Sources
PP2 PP2 can be used for PTPN11 missense variants when the gnomAD missense z score is greater than 3.09, but a verified gene-level missense z score was not available in the reviewed evidence. Details ▾Hide ▴
Rule
PP2 applies when missense z score is >3.09 in gnomAD.
Evidence considered
- PP2 rule threshold >3.09 specified in the RASopathy guidance
Still missing
- Verified PTPN11 missense z score from the applicable source.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at a level that would satisfy BS2. Details ▾Hide ▴
Rule
BS2 uses point-based evidence in this specification.
Evidence considered
- No qualifying unaffected-carrier evidence identified
Still missing
- Documented unaffected carriers or point-based BS2 evidence under the RASopathy specification.
Sources
BS4 No non-segregation data or clearly unaffected carriers within informative families were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Rule
BS4 requires informative non-segregation data.
Evidence considered
- No qualifying BS4 segregation evidence identified
Still missing
- Family-level non-segregation evidence with informative meioses.
Sources
BP2 No phase data or point-based evidence were identified to determine whether BP2 applies. Details ▾Hide ▴
Rule
BP2 uses point-based evidence in this specification.
Evidence considered
- No qualifying BP2 data identified
Still missing
- Confirmed cis/trans phase information and associated phenotype context.
Sources
BP5 No alternate molecular diagnosis or point-based evidence was identified to support BP5. Details ▾Hide ▴
Rule
BP5 uses point-based evidence in this specification.
Evidence considered
- No qualifying BP5 data identified
Still missing
- Evidence for an alternate explanation for the phenotype meeting BP5 scoring criteria.
Sources
Not applicable · 9· 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 for this variant type. Details ▾Hide ▴
Rule
PVS1 not applicable for PTPN11 in this specification.
Evidence considered
- PTPN11 missense variant p.(Lys70Arg)
- VCEP specification lists PVS1 as not applicable
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in the PTPN11 RASopathy specification for this disorder framework. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and does not cause an in-frame length change or stop-loss event, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Missense variant p.(Lys70Arg)
Sources
PP4 N/APP4 is not applicable in the PTPN11 RASopathy specification for this disorder framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the PTPN11 RASopathy specification for this disorder framework. Details ▾Hide ▴
BP1 N/ABP1 in this RASopathy framework is intended for truncating variants in genes without an established loss-of-function disease mechanism, and this variant is missense. Details ▾Hide ▴
Rule
BP1 is used here for truncating variants under specified conditions.
Evidence considered
- Missense variant p.(Lys70Arg)
Sources
BP3 N/ABP3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in this specification and was not used. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants without predicted splice impact, but this variant is missense. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or non-coding variants under specified conditions.
Evidence considered
- Missense variant p.(Lys70Arg)
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.209A>G
- Protein (HGVS p.)
- NP_001317366.1:p.(Lys70Arg)
- GRCh38
- chr12:112450389 A>G
- GRCh37
- chr12:112888193 A>G
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
2 / 1,613,656 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,656 alleles · 0 hom
| African/African American1 / 75,036 | 1.3e-05 |
| European (non-Finnish)1 / 1,179,580 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23942e-06; MAF= 0.00012%, 2/1613656 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33269e-05; MAF= 0.00133%, 1/75036 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 requires REVEL at or above 0.7 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and the available BayesDel score of 0.00798395 does not overcome the unmet REVEL threshold in this framework. Details ▾Hide ▴
Rule
PP3 for missense variants requires REVEL >= 0.7; splicing impact must match disease mechanism when relevant.
Evidence considered
- REVEL 0.668
- BayesDel 0.00798395
- SpliceAI max delta 0.00
Sources
BP4 BP4 requires REVEL at or below 0.3 for missense variants, but the REVEL score is 0.668. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the BayesDel score of 0.00798395 does not change the unmet REVEL threshold in this framework. Details ▾Hide ▴
Rule
BP4 for missense variants requires REVEL <= 0.3.
Evidence considered
- REVEL 0.668
- BayesDel 0.00798395
- SpliceAI max delta 0.00
Sources
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants without predicted splice impact, but this variant is missense. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or non-coding variants under specified conditions.
Evidence considered
- Missense variant p.(Lys70Arg)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.668. BayesDel score = 0.00798395.
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
2 / 1,613,656 recorded alleles
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/44603/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112888193-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112450389-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/PTPN11/K70R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTPN11+c.209A%3EG
- 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
This variant is present in gnomAD v4.1 (AF= 1.23942e-06; MAF= 0.00012%, 2/1613656 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33269e-05; MAF= 0.00133%, 1/75036 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) 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 = 0.668. BayesDel score = 0.00798395.
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.