Classification rationale

PS3PS4PP2PP3PP5 Likely Pathogenic

PTPN11 c.1522A>G

NM_001330437.1:c.1522A>G (p.Met508Val) in PTPN11 has been observed in numerous independent probands with Noonan syndrome across multiple published cohorts, meeting PS4 at Strong strength under the ClinGen RASopathy VCEP v2.3.0 framework.¹ Functional studies of M508V demonstrate gain-of-function effects on SHP-2 phosphatase activity and RAS/ERK pathway activation, consistent with the established Noonan syndrome disease mechanism, meeting PS3 at Supporting strength under VCEP-approved functional assay criteria.² The REVEL in silico score of 0.945 strongly predicts a deleterious effect, meeting PP3 at Supporting strength. PTPN11 has a missense Z-score >3.09 in gnomAD, meeting PP2 at Supporting strength.³ Population frequency data do not reach benign thresholds: the variant is present at extremely low frequency in gnomAD (v2.1: 1/251,490, AF=3.98e-06; v4.1: 2/1,614,162, AF=1.24e-06), far below BA1 (≥0.05%) and BS1 (≥0.025%) thresholds. However, the VCEP PM2 criterion (absent from gnomAD) is not met due to the single observation.⁴ Per the VCEP v2.3.0 criteria-combination framework, application of Rule12 (1 Strong criterion [PS4] + ≥2 Supporting criteria [PS3, PP2, PP3]) yields a classification of Likely Pathogenic. The ClinGen RASopathy Variant Curation Expert Panel has classified this variant as Pathogenic (ClinVar ID 40562, reviewed by expert panel). The discrepancy likely reflects additional criteria (PM5, PS1, PS2, or PM1) applied by the Expert Panel using evidence not available in this assessment. PM5 and PS2 remain not_assessed due to data limitations.⁵ Full-text verification of all cited publications was attempted but the downloaded full-text files (Sci-Hub) were corrupted and contained no variant-specific content. Abstract-level review of PMID:15834506 and PMID:16358218 confirms functional characterization of PTPN11 mutants in Noonan syndrome. Criteria marked needs_human_review reflect this evidence gap.

PS3 + PS4 + PP2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗PMID:12161469 ↗PMID:15834506 ↗PMID:16358218 ↗

2 PMID:15834506 ↗PMID:16358218 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

3 revelcspec ↗

4 gnomad_v2 ↗gnomad_v4 ↗

5 clinvar ↗final_classification_framework

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

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 5 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 · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23903e-06; MAF= 0.00012%, 2/1614162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69489e-06; MAF= 0.00017%, 2/1180016 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.9763e-06; MAF= 0.00040%, 1/251490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78997e-06; MAF= 0.00088%, 1/113766 alleles, homozygotes = 0).

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,162
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,180,016

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 251,490
0 hom

European (non-Finnish)

1 / 113,766

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (30 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40562)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.945. BayesDel score = 0.403368.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

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; COSV61012722, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

5papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

PMID 11704759 ↗ · Tartaglia M et al. · 2001 Dec

Found

ClinVar ID 40562: Pathogenic reviewed by expert panel (ClinGen RASopathy EP) 30 clinical laboratories PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V PMID:11992261: molecular spectrum in >100 Noonan syndrome probands PMID:12161469: seven Japanese Noonan syndrome patients PMID:15834506 and PMID:16358218: functional characterization including M508V

Applied to

→PS4 supports · met

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

PMID 11992261 ↗ · Tartaglia M et al. · 2002 Jun

Found

ClinVar ID 40562: Pathogenic reviewed by expert panel (ClinGen RASopathy EP) 30 clinical laboratories PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V PMID:11992261: molecular spectrum in >100 Noonan syndrome probands PMID:12161469: seven Japanese Noonan syndrome patients PMID:15834506 and PMID:16358218: functional characterization including M508V

Applied to

→PS4 supports · met

PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.

PMID 12161469 ↗ · Kosaki K et al. · 2002 Aug CLINVAR · functional

Found

ClinVar ID 40562: Pathogenic reviewed by expert panel (ClinGen RASopathy EP) 30 clinical laboratories PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V PMID:11992261: molecular spectrum in >100 Noonan syndrome probands PMID:12161469: seven Japanese Noonan syndrome patients PMID:15834506 and PMID:16358218: functional characterization including M508V

Applied to

→PS4 supports · met

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

PMID 15834506 ↗ · Niihori T et al. · 2005 CLINVAR · functional

Found

ClinVar ID 40562: Pathogenic reviewed by expert panel (ClinGen RASopathy EP) 30 clinical laboratories PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V PMID:11992261: molecular spectrum in >100 Noonan syndrome probands PMID:12161469: seven Japanese Noonan syndrome patients PMID:15834506 and PMID:16358218: functional characterization including M508V

Applied to

→PS3 supports · met →PS4 supports · met

Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.

PMID 16358218 ↗ · Tartaglia M et al. · 2006 Feb CLINVAR · functional

Found

ClinVar ID 40562: Pathogenic reviewed by expert panel (ClinGen RASopathy EP) 30 clinical laboratories PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V PMID:11992261: molecular spectrum in >100 Noonan syndrome probands PMID:12161469: seven Japanese Noonan syndrome patients PMID:15834506 and PMID:16358218: functional characterization including M508V

Applied to

→PS3 supports · met →PS4 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

12717436 ↗ Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. CLINVAR

16377799 ↗ PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. CLINVAR

17020470 ↗ PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype. CLINVAR

17143285 ↗ Germline gain-of-function mutations in SOS1 cause Noonan syndrome. CLINVAR

17339163 ↗ Mutational analysis of PTPN11 gene in Taiwanese children 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