The PTPN11 c.188A>G (p.Tyr63Cys) variant has been reported in ClinVar as pathogenic, including an expert panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is present at very low frequency in gnomAD, with AF 0.00120% in v2.1 and AF 0.00087% in v4.1, which is below the RASopathy BA1 and BS1 thresholds but does not meet the PTPN11 VCEP requirement for PM2 because the variant is not absent from controls.2 In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, and the RASopathy VCEP lists this assay type as an approved functional assay for PTPN11, supporting a gain-of-function effect.3 Computational evidence supports a deleterious missense effect, with REVEL 0.955 above the PTPN11 VCEP PP3 threshold of 0.7, BayesDel 0.482421, and SpliceAI showing no significant splice impact with a maximum delta score of 0.03.4
Final classification
VUS
PS3PP3PP5
PTPN11
c.188A>G
p.Tyr63Cys
This variant
The PTPN11 c.188A>G (p.Tyr63Cys) variant has been reported in ClinVar as pathogenic, including an expert panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.
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: PS3 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PS3PP3PP5
VUS
PTPN11 c.188A>G
PS3 + PP3 + PP5
→
VUS
3
PMID:15834506 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
4
revelbayesdelspliceai ↗cspec ↗
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.
Gene diagram
· NM_001330437.1 · variants mapped to exon structure
PTPN11
NM_001330437.1
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
review
Pathogenic
In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, consistent with a gain-of-function effect. The RASopathy VCEP lists SHP-2 phosphatase activity as an approved PTPN11 assay, supporting PS3 at the supporting level.
Immune complex phosphatase assay with increased activityVCEP-approved SHP-2 phosphatase assay for PTPN11
PP3
supporting
review
Pathogenic
Computational evidence supports a deleterious effect. REVEL is 0.955, which is above the PTPN11 VCEP PP3 threshold of 0.7; BayesDel is 0.482421; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting a missense rather than splice-driven interpretation.
REVEL 0.955BayesDel 0.482421SpliceAI max delta 0.03
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
PS1
No previously established pathogenic variant producing the same p.Tyr63Cys amino acid change by a different nucleotide substitution was identified, so PS1 is not met.
PS2
Published reports document de novo PTPN11 variants in Noonan syndrome cohorts, but the available evidence reviewed here does not confirm p.Tyr63Cys as de novo with the parentage information required to assign PS2.
PS4
This variant has been reported in affected individuals with Noonan syndrome, including one report identifying Tyr63Cys among seven mutation-positive Japanese cases and another reporting Tyr63Cys in two unrelated families.
PM2
This variant is present in gnomAD, with AF 0.00120% in v2.1 (3/251010 alleles) and AF 0.00087% in v4.1 (14/1613144 alleles).
PM5
No qualifying different pathogenic or likely pathogenic missense change at the same codon was identified for application of PM5.
PM6
The available evidence did not document p.Tyr63Cys as assumed de novo without full parentage confirmation, so PM6 was not assigned.
PP1
No segregation data with enough informative meioses were identified for p.Tyr63Cys, so PP1 was not assigned.
PP2
The PTPN11 specification allows PP2 when the gene missense z score is greater than 3.09, but the reviewed evidence did not provide the gene-level z score needed to confirm PP2 here.
Benign
BA1
Population frequency is below the BA1 threshold.
BS1
Population frequency is below the BS1 threshold.
BS2
The available evidence does not show this variant in the number and context of unaffected individuals required for BS2 under the RASopathy specification.
BS4
No non-segregation evidence for p.Tyr63Cys was identified, so BS4 was not assigned.
BP2
No phase data or alternate pathogenic molecular explanation was identified to support BP2.
BP4
Computational evidence does not support BP4.
BP5
No alternate molecular diagnosis or independent cause sufficient to support BP5 was identified.
N/A · 10
PVS1 · PM1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.6787e-06; MAF= 0.00087%, 14/1613144 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22777e-05; MAF= 0.00223%, 1/44888 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.19517e-05; MAF= 0.00120%, 3/251010 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43656e-05; MAF= 0.00544%, 1/18394 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00087%
· 14 / 1,613,144
0 hom · FAF 0.00043%
0 hom · FAF 0.00043%
East Asian 1 / 44,888 |
0.0022% |
Admixed American 1 / 59,982 |
0.0017% |
European (Finnish) 1 / 64,040 |
0.0016% |
South Asian 1 / 91,062 |
0.0011% |
European (non-Finnish) 10 / 1,179,260 |
0.00085% |
+ 5 not observed (Remaining individuals, Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 251,010
0 hom
0 hom
East Asian 1 / 18,394 |
0.0054% |
Admixed American 1 / 34,588 |
0.0029% |
European (non-Finnish) 1 / 113,318 |
0.00088% |
+ 5 not observed (African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (50 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 13333)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.955. BayesDel score = 0.482421.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61007856, n = 6 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & references.
Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
supporting
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
12161469 ↗
PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.
CLINVAR
12325025 ↗
PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.
CLINVAR
15928039 ↗
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.
CLINVAR
21533187 ↗
Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.
CLINVAR
22711529 ↗
Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome.
CLINVAR
24033266 ↗
A systematic approach to assessing the clinical significance of genetic variants.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
30311386 ↗
Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.
CLINVAR