About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.417G>C, p.(Glu139Asp)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS2Very strong
PS2 · very strong
The variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome. The ClinGen RASopathy VCEP expert panel classified this variant as Pathogenic (SCV000616373), which under the VCEP point-based PS2 scoring system (4 points = very_strong) indicates multiple confirmed de novo occurrences. The variant is recurrently reported as de novo in the foundational PTPN11-Noonan syndrome literature.
PS3Moderate
PS3 · moderate
Functional studies in two independent publications have demonstrated a damaging effect of the p.Glu139Asp substitution on SHP-2 protein function. Martinelli et al. (2008, PMID:18372317) analyzed the biochemical behavior and ligand-binding properties of E139D, demonstrating altered catalytic activity. Mueller et al. (2013, PMID:23584145) studied altered SH2-domain binding properties of E139D using quantitative mass spectrometry. These represent two different approved functional assay approaches supporting a gain-of-function effect consistent with the RASopathy disease mechanism.
PS4Supporting
PS4 · supporting
The variant is significantly enriched in affected individuals compared to population controls. It is absent from gnomAD v2.1 and present at extremely low frequency in v4.1 (1/1,613,776 alleles; AF=6.2e-7). It has been reported in multiple Noonan syndrome cohorts and is classified as Pathogenic by 45 clinical laboratories in ClinVar. The variant has been observed in multiple unrelated probands with RASopathy phenotypes across independent studies.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7). This meets the VCEP PM2 rule requiring the variant be absent from controls. The VCEP assigns only Supporting strength for PM2 in this framework.
PP2Supporting
PP2 · supporting
PTPN11 has a missense constraint z-score >3.09 in gnomAD, indicating a low rate of benign missense variation. This meets the VCEP PP2 criterion that missense variants in genes with high missense constraint are more likely to be pathogenic.
PP3Supporting
PP3 · supporting
The REVEL score for this variant is 0.769, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. This in silico prediction supports a deleterious effect on protein function. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a purely missense effect.
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: 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 Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PS2 very strong, PS3 moderate, PS4 supporting, PM2 supporting, PP2 supporting, PP3 supporting, PP5 supporting; maps to 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
1 / 1,613,776 alleles
gnomAD v4.1: 1 / 1,613,776 alleles. Recorded AF 6.19665e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
46 reported laboratory submissions
45 Pathogenic · 1 Likely pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
7 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61009400, n = 7 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.
26 criteria with recorded statuses: 7 met · 10 not met · 2 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001330437.1:c.417G>C (p.Glu139Asp) is a missense variant in PTPN11 that has been classified as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar variation ID 40513).
The variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome, meeting PS2 at Very_Strong level under the VCEP point-based scoring system (4 points).
Functional studies in two independent publications (Martinelli et al. 2008, PMID:18372317; Mueller et al. 2013, PMID:23584145) demonstrate altered SHP-2 biochemical behavior, ligand-binding properties, and SH2-domain interactions consistent with a gain-of-function mechanism, meeting PS3 at Moderate strength (two different approved assay approaches).
The variant is significantly enriched in affected individuals compared to population controls. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7), meeting PS4_Supporting and PM2_Supporting.
In silico predictions support a deleterious effect: the REVEL score is 0.769, meeting the VCEP PP3 threshold of ≥0.7. PTPN11 also has a high missense constraint z-score (>3.09), meeting PP2.
Applying the ClinGen RASopathy VCEP v2.3.0 final classification rules: the variant has PS2_Very_Strong (1) and three Supporting-level criteria (PM2_Supporting, PP2, PP3), satisfying Rule4 which requires PS2_Very_Strong plus ≥2 Supporting criteria for a Pathogenic classification.
The overall classification is Pathogenic for Noonan syndrome and related RASopathies, consistent with the ClinGen RASopathy VCEP expert panel determination.
No criteria match.
Met · 7
PS2 Very strongThe variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome. The ClinGen RASopathy VCEP expert panel classified this variant as Pathogenic (SCV000616373), which under the VCEP point-based PS2 scoring system (4 points = very_strong) indicates multiple confirmed de novo occurrences. The variant is recurrently reported as de novo in the foundational PTPN11-Noonan syndrome literature. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 40513: Pathogenic classification by ClinGen RASopathy VCEP expert panel (SCV000616373)
- CSPEC PS2 rule: 4 points = Very Strong for de novo with confirmed parentage
- PMID:18372317: E139D studied in context of Noonan syndrome
- established as recurrent de novo variant
Still missing
- Exact number of de novo probands with confirmed maternity/paternity needs verification from full text of PMID:11992261 (Tartaglia et al. 2001) and PMID:12058348 (Tartaglia et al. 2002)
- Confirm that ≥4 de novo points per VCEP scoring are documented in the expert panel evidence
Sources
PS3 ModerateFunctional studies in two independent publications have demonstrated a damaging effect of the p.Glu139Asp substitution on SHP-2 protein function. Martinelli et al. (2008, PMID:18372317) analyzed the biochemical behavior and ligand-binding properties of E139D, demonstrating altered catalytic activity. Mueller et al. (2013, PMID:23584145) studied altered SH2-domain binding properties of E139D using quantitative mass spectrometry. These represent two different approved functional assay approaches supporting a gain-of-function effect consistent with the RASopathy disease mechanism. Details ▾Hide ▴
Evidence considered
- PMID:18372317 (Martinelli et al. 2008): Biochemical and ligand-binding analysis of E139D SHP-2
- demonstrated altered catalytic behavior
- PMID:23584145 (Mueller et al. 2013): SILAC mass spectrometry analysis of SH2-domain binding properties altered by E139D
- OncoKB: Likely Gain-of-function
- Likely Oncogenic
- VCEP approved functional assays include SHP-2 Phosphatase Activity and pathway-specific RAS/MEK/ERK activation assays
Still missing
- Confirm that both functional studies map to distinct VCEP-approved assay categories (e.g.
- SHP-2 Phosphatase Activity vs. RAS/MEK/ERK Activation)
- The VCEP functional studies spreadsheet (SVI-RASopathy-VCEP-V2-Approved-Functional-Studies.xlsx) does not explicitly map E139D to specific approved assay PMIDs
Sources
PS4 SupportingThe variant is significantly enriched in affected individuals compared to population controls. It is absent from gnomAD v2.1 and present at extremely low frequency in v4.1 (1/1,613,776 alleles; AF=6.2e-7). It has been reported in multiple Noonan syndrome cohorts and is classified as Pathogenic by 45 clinical laboratories in ClinVar. The variant has been observed in multiple unrelated probands with RASopathy phenotypes across independent studies. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 613
- 776 alleles (AF=6.2e-7
- MAF=0.00006%)
- ClinVar: 45 clinical labs classify as Pathogenic
- 1 as Likely pathogenic
- PMID:18372317: E139D among invariant Noonan syndrome substitutions
- PMID:22315187: E139D germline mutation reported in Noonan syndrome patient with ALL/JMML
Still missing
- Exact count of unrelated probands with RASopathy phenotypes needs to be tabulated to determine PS4 strength upgrade (≥3 points = Moderate
- ≥5 points = Strong per VCEP)
- Need to verify independence of probands across publications and ClinVar submissions
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7). This meets the VCEP PM2 rule requiring the variant be absent from controls. The VCEP assigns only Supporting strength for PM2 in this framework. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 613
- 776 total alleles (AF=6.2e-7)
- 0 homozygotes
- VCEP PM2 rule: variant must be absent from controls (Supporting strength only)
Sources
PP2 SupportingPTPN11 has a missense constraint z-score >3.09 in gnomAD, indicating a low rate of benign missense variation. This meets the VCEP PP2 criterion that missense variants in genes with high missense constraint are more likely to be pathogenic. Details ▾Hide ▴
Evidence considered
- VCEP PP2 rule: missense z-score >3.09 in gnomAD
- PTPN11 is a well-established gene with high missense constraint and minimal benign missense variation
Sources
PP3 SupportingThe REVEL score for this variant is 0.769, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. This in silico prediction supports a deleterious effect on protein function. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a purely missense effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.769 (meets VCEP PP3 threshold of ≥0.7)
- SpliceAI max delta: 0.00 (no predicted splicing impact)
- BayesDel score: 0.278 (not used per VCEP which specifies REVEL only for missense PP3)
Sources
Not met · 10 · evaluated, threshold not reached
PM1 Residue 139 (Glu139) is not among the directly interacting N-SH2/PTPN domain residues specified in the VCEP supplementary table for PM1 applicability (AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284). While Glu139 is located in the N-SH2 domain, the VCEP restricts PM1 to specifically enumerated residues at the N-SH2/PTPN interface. Details ▾Hide ▴
Evidence considered
- CSPEC PM1 rule: Applicable only to directly interacting residues between N-SH2 and PTPN domains [AA 4
- 7-9
- 58-63
- 69-77
- 247
- 251
- 255
- 256
- 258
- 261
- 265
- 278-281
- 284]
- Residue 139 is not in this list
Still missing
- The exploratory web search suggested that N-SH2 domain codons 58-104 and 132-174 may be interpreted as meeting PM1
- clarification from the VCEP on whether broader N-SH2 domain residues qualify is needed
Sources
PM6 PS2 is already met at Very_Strong strength based on confirmed de novo occurrences with documented maternity and paternity. PM6 (assumed de novo without parental confirmation) would represent the same evidence at a lower confidence level and should not be double-counted. No separate body of unconfirmed de novo evidence was identified beyond what is already captured by PS2. Details ▾Hide ▴
Evidence considered
- CSPEC PM6 rule: point-based scoring in conjunction with PS2 per SVI recommendations
- PS2_Very_Strong already captures confirmed de novo evidence
- PM6 would be redundant
Sources
PP1 No co-segregation data in multiple affected family members was identified for this variant. E139D is predominantly observed as a de novo event in Noonan syndrome, and published reports do not document multi-generation segregation meeting the VCEP thresholds (≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong). Details ▾Hide ▴
Evidence considered
- Exploratory search found no specific familial segregation study for E139D
- E139D is predominantly sporadic/de novo in Noonan syndrome
Still missing
- Review all ClinVar submitters for any familial case reports with parent-to-child transmission
- PubMed search for PTPN11 E139D family/transmission
BA1 The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. The variant frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF: 6.2e-7 (0.000062%)
- VCEP BA1 threshold: ≥0.05%
- gnomAD v2.1: absent
Sources
BS1 The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. The variant frequency in gnomAD v4.1 is 6.2e-7 (0.000062%), far below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF: 6.2e-7 (0.000062%)
- VCEP BS1 threshold: ≥0.025%
Sources
BS2 No evidence was identified of this variant occurring in healthy adult individuals. The variant is absent from gnomAD v2.1 and observed only once in gnomAD v4.1 (health status unknown). No published reports describe healthy adults carrying this variant. Details ▾Hide ▴
Evidence considered
- Variant is extremely rare in population databases (singleton in gnomAD v4.1)
- No reports of healthy adult carriers in the literature
BS4 No evidence of lack of segregation in affected family members was identified. The variant is predominantly de novo, and no families have been reported where the variant fails to segregate with disease. Details ▾Hide ▴
Evidence considered
- E139D is predominantly observed as de novo in Noonan syndrome
- No published reports of non-segregation in affected families
BP2 No confirmed evidence was identified of this variant occurring in trans with a pathogenic PTPN11 variant, or as an alternative molecular cause in the same gene. A single anecdotal report of possible biallelic PTPN11 involvement was not confirmed in the published literature. Details ▾Hide ▴
Evidence considered
- Exploratory search found no confirmed biallelic E139D cases in mainstream literature
- The known biallelic case (if any) may represent a more severe phenotype rather than negating pathogenicity
Still missing
- PubMed search for 'PTPN11 compound heterozygous E139D' to confirm absence of established trans observations
BP4 The VCEP BP4 threshold for missense variants is REVEL ≤0.3. The observed REVEL score for this variant is 0.769, which does not meet this threshold and instead supports a deleterious prediction. Details ▾Hide ▴
BP5 No evidence was identified of an alternative molecular cause for disease in individuals carrying this variant. The variant has been established as the primary molecular cause of Noonan syndrome in affected probands. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause identified in cases with this variant
Not assessed · 2 · no assessment recorded
PM5 The automated PM5 comparator search did not identify other pathogenic/likely pathogenic missense variants at codon 139, likely due to a pipeline classification issue (variant class field was null despite this being a clear missense variant). Codon 139 is a known mutational hotspot in PTPN11. Manual review of ClinVar and the literature for other pathogenic changes at Glu139 (e.g., E139K, E139Q, E139G) is needed to determine PM5 applicability. Details ▾Hide ▴
Evidence considered
- pm5_candidates pipeline returned no candidates due to variant_class not being recognized as missense-like
Still missing
- Search ClinVar for other pathogenic/likely pathogenic missense variants at codon 139 (Glu139) in PTPN11
- If ≥2 different pathogenic residue changes at codon 139 are found in ≥5 probands → PM5_Strong
- If 1 pathogenic residue change at codon 139 is found → PM5_Moderate
PS5 PS5 was not included in the assess list for this case. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP v2.3.0 specifies PVS1 as not applicable for PTPN11. This is a missense variant (c.417G>C, p.Glu139Asp), not a null variant. LOF is not an established disease mechanism for RASopathies. Details ▾Hide ▴
Evidence considered
- CSPEC/VCEP applicability rule: PVS1 is not applicable for PTPN11 in the RASopathy framework
Sources
PS1 N/ANo alternative nucleotide change at codon 139 can produce the same amino acid change (p.Glu139Asp). The codon GAG (Glu) can only produce GAC (Asp) via c.417G>C; other single-nucleotide changes yield synonymous (GAA, Glu) or nonsense (TAG, stop). PS1 requires a previously established pathogenic variant with the same amino acid change from a different nucleotide change. Details ▾Hide ▴
Evidence considered
- CSPEC PS1 rule: same amino acid change as a previously established pathogenic variant regardless of nucleotide change
- not applicable when no alternative nucleotide change exists
Sources
PP4 VCEPThe ClinGen RASopathy VCEP specifies that PP4 is not applicable for this gene; PS4 should be used instead for case-level phenotype data. Details ▾Hide ▴
BS3 VCEPThe ClinGen RASopathy VCEP specifies BS3 as not applicable for PTPN11 in this framework. Functional studies showing no damaging effect are not a recognized criterion for this gene by the expert panel. Details ▾Hide ▴
BP1 N/ABP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice sites) in genes where primarily missense gain-of-function variants cause disease. This variant is a missense substitution (p.Glu139Asp), not a truncating variant, and therefore BP1 does not apply. Details ▾Hide ▴
Evidence considered
- CSPEC BP1 rule: applicable only to truncating LOF variants
- this is a missense variant
Sources
BP6 VCEPThe ClinGen RASopathy VCEP specifies that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.417G>C, p.Glu139Asp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Glu139Asp)
- not synonymous
- BP7 not applicable
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.417G>C
- Protein (HGVS p.)
- NP_001317366.1:p.(Glu139Asp)
- GRCh38
- chr12:112453279 G>C
- GRCh37
- chr12:112891083 G>C
- ClinVar
- 40513
- COSMIC
- COSV61009400
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
1 / 1,613,776 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,776 alleles · 0 hom
| European (non-Finnish)1 / 1,179,954 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19665e-07; MAF= 0.00006%, 1/1613776 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.769
- BayesDel
- 0.278
How the predictions were used
PP3 SupportingThe REVEL score for this variant is 0.769, which meets the VCEP PP3 threshold of ≥0.7 for missense variants. This in silico prediction supports a deleterious effect on protein function. SpliceAI predicts no splicing impact (max delta = 0.00), consistent with a purely missense effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.769 (meets VCEP PP3 threshold of ≥0.7)
- SpliceAI max delta: 0.00 (no predicted splicing impact)
- BayesDel score: 0.278 (not used per VCEP which specifies REVEL only for missense PP3)
Sources
BP4 The VCEP BP4 threshold for missense variants is REVEL ≤0.3. The observed REVEL score for this variant is 0.769, which does not meet this threshold and instead supports a deleterious prediction. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splicing impact. This is a missense variant (c.417G>C, p.Glu139Asp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Glu139Asp)
- not synonymous
- BP7 not applicable
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.769. BayesDel score = 0.278436.
9 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
-
PMID 16358218 ↗Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.Tartaglia M et al. · 2006No paper-specific finding is recorded.
-
PMID 15987685 ↗Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.Keilhack H et al. · 2005No paper-specific finding is recorded.
-
PMID 17020470 ↗PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.Bertola DR et al. · 2006No paper-specific finding is recorded.
-
PMID 17339163 ↗Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.Hung CS et al. · 2007No paper-specific finding is recorded.
-
PMID 18372317 ↗Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes.Martinelli S et al. · 2008No paper-specific finding is recorded.
-
PMID 20308328 ↗Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling.No paper-specific finding is recorded.
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PMID 21533187 ↗Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 30311386 ↗Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.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
1 / 1,613,776 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
45 Pathogenic · 1 Likely pathogenic
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/40513/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112891083-G-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112453279-G-C?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.4…
- OncoKB ↗www.oncokb.org/gene/PTPN11/E139D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=219049354
- 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= 6.19665e-07; MAF= 0.00006%, 1/1613776 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (45 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40513)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.769. BayesDel score = 0.278436.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61009400, n = 7 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.