The PTPN11 NM_002834.5:c.922A>G (NP_002825.3:p.(Asn308Asp)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61006575, n = 12 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: P.N308D shows increased phosphatase activity and prolonged ERK2 activation in two different VCEP-approved assay types. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen RASopathy Variant Curation Expert Panel; ClinVar ID 13326).
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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.PTPN11 encodes SHP2, a protein tyrosine phosphatase that helps regulate signaling pathways controlling cell growth, development, metabolism, and movement. Inherited changes in PTPN11 are associated with Noonan syndrome and LEOPARD syndrome, which can increase the risk of juvenile myelomonocytic leukemia and related blood disorders. PTPN11 acts as an oncogene, and acquired changes in the gene occur in several cancers, especially juvenile myelomonocytic leukemia.
The recorded framework is ClinGen PTPN11 VCEP v2.3. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at Moderate: p.N308D shows increased phosphatase activity and prolonged ERK2 activation in two different VCEP-approved assay types.
Met at Moderate: the variant occurred in multiple unrelated Noonan syndrome patients and was absent from more than 200 controls, satisfying the VCEP rare-variant pathway.
Met: REVEL 0.838 meets the PTPN11 VCEP PP3 missense threshold of ≥0.7.
Not applicable: the PTPN11 VCEP prohibits use of PP5, regardless of published pathogenic classifications.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 and PS4 at moderate plus PP3 and PP5 at supporting do not satisfy any PTPN11 VCEP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 12 / 1,612,192 alleles. Recorded AF 7.44328e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.19313e-05; MAF= 0.00119%, 3/251440 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000162973; MAF= 0.01630%, 1/6136 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.838. Refer to the recorded PP3/BP4 rationale for interpretation.
70 Pathogenic · 2 pathogenic. ClinVar API review status: reviewed by expert panel.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61006575, n = 12 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested criteria are not applicable under the governing PTPN11 RASopathy VCEP specification: PVS1 is explicitly excluded, while PM4 and BP3 require variant classes that do not include this missense substitution.
PS4 is met at Moderate strength under the VCEP rare-variant pathway: multiple unrelated Noonan syndrome patients carried c.922A>G/p.N308D and the variant was absent from more than 200 controls in one report.
PP4, PP5, and BP6 are not applicable under the PTPN11 VCEP specification.
BP5 is not assessed because no alternative molecular cause or VCEP point total is documented.
The VCEP missense-specific REVEL score supports PP3 and excludes BP4; BP7 is outside scope for this missense variant.
No criteria match.
The VCEP approves MEK activation, ERK activation, and SHP-2 phosphatase activity assays for PTPN11 functional evaluation. The governing functional-studies table lists N308D as a pathogenic validation control in the PTPN11 MEK and ERK activation assays and in the approved SHP-2 phosphatase activity assay. Variant-specific studies independently show that p.N308D has increased SHP2 phosphatase activity and prolonged EGF-dependent ERK2 activation. These are two different approved assay types supporting a damaging gain-of-function effect, meeting the VCEP Moderate PS3 calibration.
Two or more different approved assays.
The VCEP defines PS4 as increased prevalence in affected individuals versus controls, with OR/RR >5.0 and a confidence interval excluding 1.0; it also permits moderate evidence for very rare variants observed in multiple unrelated patients with the same phenotype and absent from controls. This variant was independently reported in multiple unrelated Noonan syndrome cohorts: 4 affected individuals in the 11704759 study, 17 affected individuals in the 11992261 cohort, 6 unrelated families in the 15001945 cohort, and 5 subjects from one family in 12634870. PMID:11704759 explicitly states that reported mutations were absent from more than 200 control individuals. I evaluated the case-control counts: the published reports do not provide a complete 2x2 table with the number of non-carrier affected individuals, so a finite OR and 95% CI cannot be calculated from those reports; the available data therefore support the VCEP's rare-variant moderate-evidence pathway rather than the quantitative >5.0 pathway. The reported affected-case recurrence and absence in controls are consistent with the RASopathy phenotype, but do not justify Strong strength without a VCEP point total or complete quantitative case-control data.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. ... Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. ... ≥3 points.
The VCEP scope first identifies the variant as missense, NM_002834.5:c.922A>G (p.Asn308Asp). For missense variants, the governing PP3 rule names REVEL and requires REVEL ≥ 0.7; it does not require a splice prediction on that missense path. The recorded REVEL score is 0.838, which meets the VCEP threshold. SpliceAI is not counted because it is not the predictor named for the missense path, and the same computational prediction is not double-counted across criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The variant is p.Asn308Asp, but the available same-residue review identified no different-nucleotide variant producing the same amino-acid change with an established pathogenic classification. The PM5 comparator collection reported zero same-residue candidates, so the VCEP PS1 condition is not met.
Same amino acid change as a previously established pathogenic variant in _PTPN11_ regardless of nucleotide change.
The VCEP limits PM1 to directly interacting N-SH2/PTP residues 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, and 284. The variant is at residue 308, outside every listed region. The authoritative domain_tables entry for PTPN11 is empty, and no VCEP-named hotspot route applies.
Applicable only to critical and well-established functional domains available in the supplementary table (Directly interacting residues between N-SH2 and PTPN domains [AA 4, AA 7-9, AA 58-63, AA 69-77, AA 247, AA 251, AA 255, AA 256, AA 258, AA 261, AA 265, AA 278-281, AA 284]). Not applicable to specific amino acid residues (see PM5).
The governing PTPN11 VCEP PM2 rule requires the variant to be absent from controls in gnomAD. This variant is present in both available default all-comers gnomAD datasets: gnomAD v2.1 has 3/251440 alleles (AF 1.19313e-05; homozygotes 0), and gnomAD v4.1 has 12/1612192 alleles (AF 7.44328e-06; homozygotes 0). Because the VCEP rule does not specify a non-cancer or exome-only subset, the all-comers entries are the governing default, and PM2 is not met.
The variant must be absent from controls (gnomAD).
The VCEP PM5 rule requires at least one different likely pathogenic residue change at the same codon for Moderate strength, or at least two different likely pathogenic residue changes observed in at least five probands for Strong strength. The comparator collection found zero same-residue candidates, so neither threshold is met.
1 [likely] pathogenic residue change at the same codon.
The governing PTPN11 VCEP BA1 rule requires a gnomAD filtering allele frequency of at least 0.05%. The available gnomAD data do not reach this threshold: gnomAD v2.1 reports an overall AF of 1.19313e-05 (0.00119%) and highest observed population AF of 0.000162973 (0.01630%, 1/6136 alleles), while gnomAD v4.1 reports an overall AF of 7.44328e-06 (0.00074%), highest observed population AF of 6.75813e-05 (0.00676%, 2/29594 alleles), and grpmax FAF of 1.24e-06. Therefore BA1 is not met.
GnomAD filtering allele frequency >=0.05%.
The governing PTPN11 VCEP BS1 rule requires a gnomAD filtering allele frequency of at least 0.025%. The available frequencies remain below this threshold: gnomAD v2.1 has a highest observed population AF of 0.000162973 (0.01630%, 1/6136 alleles), and gnomAD v4.1 has a highest observed population AF of 6.75813e-05 (0.00676%, 2/29594 alleles) with grpmax FAF 1.24e-06. Therefore BS1 is not met.
GnomAD filtering allele frequency >=0.025%.
The VCEP scope first identifies the variant as missense, NM_002834.5:c.922A>G (p.Asn308Asp). For missense variants, the governing BP4 rule names REVEL and requires REVEL ≤ 0.3. The recorded REVEL score is 0.838, so the variant does not meet the VCEP BP4 threshold. SpliceAI is not counted because it is not the predictor named for the missense path, and a no-splice-impact result would not override the missense REVEL result.
For missense variants: REVEL ≤ 0.3.
The VCEP assigns PS2 strength by de novo evidence points: 4 points for Very Strong, 2 points for Strong, and 1 point for Moderate. The available evidence reports the variant in a sporadic case and contains an unverified lead describing confirmed and unconfirmed de novo occurrences, but it does not provide auditable parental-test results or enough verified information to assign de novo points.
4 Points. ... 2 Points. ... 1 Point.
The VCEP assigns PM6 strength by 2 points for Strong, 1 point for Moderate, or 0.5 points for Supporting. No verified de novo occurrence without confirmed parental testing is documented in the auditable evidence available for this case; therefore the VCEP PM6 point rule cannot be applied.
2 Points. ... 1 Point. ... 0.5 Points.
The VCEP requires at least 3 informative meioses for Supporting, at least 5 for Moderate, or at least 7 for Strong PP1. PMID:11992261 reports that the variant cosegregated with the Noonan phenotype in a large three-generation family, and the available curation wording says more than 7 family members, but neither source establishes the number of informative meioses; affected-family-member counts cannot be substituted for meioses.
≥7 informative meioses. ... ≥5 informative meioses. ... ≥3 informative meioses.
The VCEP requires a missense z score greater than 3.09 in gnomAD. No PTPN11 missense z score is available in the case evidence, so this criterion cannot be evaluated without substituting an unapproved metric or threshold.
Missense z score is >3.09 in gnomAD.
The governing PTPN11 VCEP BS2 entry specifies only point values (-4 Points or -1 Point) and does not provide an evaluable population observation rule in the case materials. The gnomAD records show no homozygotes, but the available evidence does not establish the VCEP-required BS2 point assignment or demonstrate unaffected individuals carrying the variant. BS2 is therefore not assessed.
\-4 Points. ... \-1 Point.
The VCEP BS4 rule requires only one informative meiosis. The available evidence reports cosegregation in a large family but does not document an informative non-segregating meiosis or an unaffected tested relative carrying the variant; absence of such documentation is insufficient to call BS4 not_met or met.
Requires only one informative meiosis.
The VCEP provides BP2 only as point thresholds: strong at ≥ (-4) points, moderate at ≥ (-2) points, and supporting at ≥ (-1) point. The available evidence reports familial occurrence and cosegregation of c.922A>G, but does not document a second pathogenic variant in cis or trans, its phase, or an applicable BP2 point assignment. BP2 therefore cannot be evaluated without substituting an external rule or inferring phase.
≥ (-4) Points. ... ≥ (-2) Points. ... ≥ (-1) Point.
The VCEP requires BP5 evidence for an alternative molecular cause of a RASopathy in a different gene, with a phenotype consistent with the expected severity, or a phenotype inconsistent with RASopathy fully explained by a different causative variant. The available case evidence documents PTPN11 c.922A>G in Noonan syndrome but does not document an alternative causative variant in another gene or a fully explanatory alternative diagnosis. No BP5 points can therefore be assigned. The VCEP's numeric directions are explicitly ≥ (-4) Points for Strong, ≥ (-2) Points for Moderate, and ≥ (-1) Point for Supporting; no point value is available to test against those operators.
Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing). ... ≥ (-4) Points. ... ≥ (-2) Points. ... ≥ (-1) Point.
Not applicable under the PTPN11 RASopathy VCEP specification: PVS1 is explicitly excluded for this framework because LOF/haploinsufficiency has not been clearly identified as the disease mechanism for the RASopathy spectrum. The variant is NM_002834.5:c.922A>G, a missense substitution producing NP_002825.3:p.(Asn308Asp) in exon 8, not a predicted LOF allele requiring a PVS1 strength assignment.
LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria.
The ClinGen RASopathy VCEP PTPN11 Version 2.3 specification explicitly marks PM3 as not applicable. Therefore, phase or affected-proband observations cannot activate PM3 under this governing framework, regardless of the reported familial observations for NM_002834.5:c.922A>G (p.Asn308Asp).
Not Applicable
Not applicable because the VCEP limits PM4 to protein length changes caused by in-frame deletions/insertions in a non-repeat region or stop-loss variants. NM_002834.5:c.922A>G is a missense substitution producing p.(Asn308Asp), with no protein length change, so the PM4 rule does not apply.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... No known repetitive areas in gene. Use as described.
The PTPN11 VCEP marks PP4 as not applicable and directs evaluation to PS4.
Not applicable, see PS4.
BS3 is explicitly marked Not applicable in the ClinGen RASopathy Expert Panel PTPN11 Version 2.3 specification. Therefore, the normal-function branch is not evaluated even though the approved functional-studies table documents assay controls and includes a BS3/NA notation for the SHP-2 assay.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The VCEP BP1 rule restricts use to truncating variants, including nonsense, frameshift, canonical splice-site, initiation-codon, whole-gene, or multi-exon deletions, in specified genes. This variant is missense p.Asn308Asp, so BP1 is not applicable.
This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.
Not applicable under the VCEP specification. BP3 is limited to in-frame deletions or insertions in a repetitive region without a known function; c.922A>G is a missense substitution producing p.(Asn308Asp), not an in-frame deletion or insertion.
No known benign repetitive areas in RASopathy genes. ... In frame-deletions/insertions in a repetitive region without a known function.
The PTPN11 VCEP marks BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule applies to synonymous variants and also to intronic positions except canonical splice sites or non-coding variants. NM_002834.5:c.922A>G is a missense variant producing p.Asn308Asp, so it is outside BP7 scope. BP7 is therefore not_applicable before any splice-prediction or conservation evidence is considered.
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
Every interpreted variant in PTPN11, mapped onto the exon structure of NM_002834.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish2 / 29,594 | 6.8e-05 |
| Remaining individuals3 / 62,424 | 4.8e-05 |
| European (Finnish)2 / 64,026 | 3.1e-05 |
| European (non-Finnish)5 / 1,178,366 | 4.2e-06 |
| Remaining individuals1 / 6,136 | 0.00016 |
| European (Finnish)1 / 21,648 | 4.6e-05 |
| Admixed American1 / 34,592 | 2.9e-05 |
This variant is present in gnomAD v4.1 (AF= 7.44328e-06; MAF= 0.00074%, 12/1612192 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 6.75813e-05; MAF= 0.00676%, 2/29594 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
This variant is present in gnomAD v2.1 (AF= 1.19313e-05; MAF= 0.00119%, 3/251440 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000162973; MAF= 0.01630%, 1/6136 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The VCEP scope first identifies the variant as missense, NM_002834.5:c.922A>G (p.Asn308Asp). For missense variants, the governing PP3 rule names REVEL and requires REVEL ≥ 0.7; it does not require a splice prediction on that missense path. The recorded REVEL score is 0.838, which meets the VCEP threshold. SpliceAI is not counted because it is not the predictor named for the missense path, and the same computational prediction is not double-counted across criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The VCEP scope first identifies the variant as missense, NM_002834.5:c.922A>G (p.Asn308Asp). For missense variants, the governing BP4 rule names REVEL and requires REVEL ≤ 0.3. The recorded REVEL score is 0.838, so the variant does not meet the VCEP BP4 threshold. SpliceAI is not counted because it is not the predictor named for the missense path, and a no-splice-impact result would not override the missense REVEL result.
For missense variants: REVEL ≤ 0.3.
The VCEP BP7 rule applies to synonymous variants and also to intronic positions except canonical splice sites or non-coding variants. NM_002834.5:c.922A>G is a missense variant producing p.Asn308Asp, so it is outside BP7 scope. BP7 is therefore not_applicable before any splice-prediction or conservation evidence is considered.
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.838. BayesDel score = 0.144325.
8 paper records listed. 6 cited in the classification.
A transition at nt 922 in exon 8 is found in families NS-A, NS-V and N-7, as well as in individual NS-B (sporadic case).
Location Results, page 466; Table 1
Context PTPN11 mutation screening by bidirectional sequencing in familial and sporadic individuals with Noonan syndrome; A922G was confirmed by PCR amplification followed by EcoRV digestion.
The ArG transition at position 922 in exon 8, predicting the Asn308Asp substitution within the PTP domain, was the most common mutation, accounting for one-third of the total.
Location Results, 'Spectrum of PTPN11 Mutations'; Table 3; Figure 1A; Results, 'Genotype-Phenotype Correlation'; Discussion
Context PTPN11 coding-region mutation screening with DHPLC and bidirectional sequencing, cosegregation analysis, and control exclusion in a cohort of 119 individuals with Noonan syndrome, including a large three-generation family.
"the A922G change lies in exon 8" ... "A922G which was present in four index patients and one relative."
Location Results, paragraphs 2 and 4; Table 1, Exon 8 row
Context PTPN11 mutation screening of 96 patients with Noonan syndrome, including 79 index patients and 17 relatives, using DHPLC and bidirectional sequencing.
In the present study, we investigated the pathogenic role of NS-associated PTPN11 mutations further. In addition to the c.922A4G/p.N308D substitution, which is the most common NS mutation, SHP2 proteins were engineered to carry the c.214G4T/p.A72S and c.844A4G/p.I282V changes located on the interacting surfaces of the N-terminal Src homology 2 and protein tyrosine phosphatase domains, respectively.
Location Introduction; Results sections titled ‘Mutant SHP2 Immune Complexes Exhibit Increased Protein Tyrosine Phosphatase Activity’ and ‘SHP2 Mutants Induce Prolonged ERK2 Activation in Response to EGF’
Context Functional studies used transient expression of wild-type or p.N308D SHP2-V5 in COS-7 cells with serum starvation and EGF stimulation; assays included immune-complex phosphatase activity and ERK2 kinase activity, with WT and catalytically inactive controls.
The known recurrent mutation N308D, which accounted for 31% in the study of Tartaglia et al,5 was the most common one in our cohort as well (18%).
Location Results, Spectrum of Identified PTPN11 Mutations; Table I; Genotype-Phenotype Correlation
Context Prospective cohort of 57 unrelated pediatric patients meeting clinical inclusion criteria for Noonan syndrome; six unrelated families carried N308D.
Mild activation (two-fold to 3.9-fold) was observed in the immune complexes derived from cells transfected with constructs harboring the Y63C or Q79R mutation in the N-SH2 domain and constructs with the I282V, N308D, S502T, or M504V mutation in the PTP domain.
Location Results, ‘Phosphatase activities of mutants identified in NS’; Table 1, patient 13; Table 2, PTP domain, codon 308
Context Nine PTPN11 mutations from patients with Noonan syndrome were tested after transfection of wild-type or mutant FLAG-tagged SHP2 constructs into COS7 cells; phosphatase activity was normalized to wild type.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 7.44328e-06; MAF= 0.00074%, 12/1612192 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 6.75813e-05; MAF= 0.00676%, 2/29594 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
This variant is present in gnomAD v2.1 (AF= 1.19313e-05; MAF= 0.00119%, 3/251440 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000162973; MAF= 0.01630%, 1/6136 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (70 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 13326)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.838. BayesDel score = 0.144325.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61006575, n = 12 times).
This variant lies in a statistically significant hotspot.