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Initialising…

PTPN11

Final classification

Benign

PTPN11 c.1052G>A · p.Arg351Gln

PTPN11

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.

Gene

PTPN11

Transcript

NM_001330437.1

HGVS · transcript:coding

NM_001330437.1:c.1052G>A

Consequence

N/A

GRCh38

chr12:112477975 G>A

GRCh37

chr12:112915779 G>A

Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP6 supporting benign; maps to Benign. ▾

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BP6 supporting benign; maps to Benign.

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 ↗

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

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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