Classification rationale

PS3PP3PP5 VUS

PTPN11 c.188A>G

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

PS3 + PP3 + PP5 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 PMID:15834506 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗

4 revelbayesdelspliceai ↗cspec ↗

Gene diagram · NM_001330437.1 · variants mapped to exon structure

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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

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)

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.955. BayesDel score = 0.482421.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

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. 10 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:15834506

PMID PMID:15834506 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 10 PMIDs not cited in assessment

15834506 ↗ Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. ONCOKB

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

24219368 ↗ MAPK activation in mature cataract associated with Noonan syndrome. 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