Classification rationale

BA1BP6 Benign

PTPN11 c.1052G>A

The PTPN11 c.1052G>A (p.Arg351Gln) variant has been observed in somatic cancers in COSMIC and is reported in ClinVar with an expert-panel benign classification.¹ In population data, this variant is present in gnomAD v2.1 with overall AF 0.04255% (107/251446), South Asian AF 0.34303% (105/30610), and grpmax FAF 0.28984%, which is above the PTPN11 VCEP BA1 threshold of 0.05%; it was not observed in gnomAD v4.1.² Available computational evidence does not meet the PTPN11 VCEP PP3 threshold because REVEL is 0.516, below the required 0.7, while SpliceAI predicts no significant splice impact with a max delta score of 0.00.³

BA1 + BP6 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 revelspliceai ↗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 · 2 applied · 17 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 · 2

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

The PTPN11 VCEP BA1 threshold is gnomAD filtering allele frequency at least 0.05%. In gnomAD v2.1, this variant has grpmax FAF 0.28984% and highest observed population AF 0.34303% in South Asian samples (105/30610), which are above the 0.05% threshold, so BA1 is met.

gnomAD v2.1 grpmax FAF 0.0028984100000000006.gnomAD v2.1 South Asian AF 0.003430251551780464 (105/30610).gnomAD v4.1 absent.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

VCEP marks BP6 not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 7 not met · 10 not assessed

Pathogenic

PS1 Available reviewed sources did not identify a previously established pathogenic PTPN11 variant with the same amino acid change, so PS1 is not met.

PS2 No confirmed de novo germline RASopathy observation with maternity and paternity confirmation was identified in the reviewed sources, so PS2 cannot be applied from the currently available evidence.

PS3 The VCEP allows PS3 only when approved functional assays support a damaging effect.

PS4 The available reports and cited publications concern somatic leukemia or JMML settings, and no de-duplicated germline RASopathy case enrichment versus controls was identified.

PM1 For PTPN11, PM1 is limited to specific listed residues and residue ranges in the N-SH2/PTP interaction interface.

PM2 PM2 requires absence from gnomAD.

PM5 Available reviewed sources did not identify a different pathogenic or likely pathogenic missense change at codon 351 in PTPN11, so the same-residue missense comparator requirement for PM5 is not met.

PM6 No assumed de novo germline RASopathy observation without maternity and paternity confirmation was identified in the reviewed sources, so PM6 cannot be applied.

PP1 No segregation data with informative meioses were identified for this variant, so PP1 cannot be applied.

PP2 PP2 requires a gnomAD missense z score greater than 3.09.

PP3 For PTPN11 missense variants, the VCEP PP3 threshold is REVEL at least 0.7.

Benign

BS1 This variant exceeds the BS1 frequency threshold, but BA1 is already met and is the more appropriate stand-alone population criterion, so BS1 was not separately counted.

BS2 Although the variant is present in population databases, no reviewed source documented phenotyped healthy individuals meeting the VCEP BS2 requirements, so BS2 was not applied.

BS4 No informative family data showing lack of segregation were identified in the reviewed sources, so BS4 cannot be applied.

BP2 No evidence was identified showing this variant with a qualifying alternative pathogenic variant in the same gene with the phase and phenotype context required for BP2, so BP2 cannot be applied.

BP4 For PTPN11 missense variants, the VCEP BP4 threshold is REVEL 0.3 or lower.

BP5 No evidence was identified showing a fully explanatory alternative molecular cause of a RASopathy or a non-RASopathy explanation in the same individual, so BP5 cannot be assessed from the current evidence.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · PP5 · BS3 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000425539; MAF= 0.04255%, 107/251446 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00343025; MAF= 0.34303%, 105/30610 alleles, homozygotes = 0); grpmax FAF= 0.00289841.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

0.043% · 107 / 251,446
0 hom · FAF 0.29%

South Asian 105 / 30,610	0.34%
East Asian 1 / 18,394	0.0054%
European (non-Finnish) 1 / 113,734	0.00088%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40541)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.516. BayesDel score = 0.0913187.

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; COSV61012894, n = 5 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

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

15710330 ↗ Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. CLINVAR

19179468 ↗ Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

14644997 ↗ Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. CLINVAR

15385933 ↗ PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. CLINVAR

17972951 ↗ Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. CLINVAR

19047918 ↗ Correlation of clinical features with the mutational status of GM-CSF signaling pathway-related genes in juvenile myelomonocytic leukemia. CLINVAR

24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR

27069254 ↗ The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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