The PTPN11 c.53A>G (p.Asn18Ser) variant has not been observed in COSMIC and has been reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel, with additional benign and likely benign clinical laboratory submissions.1 This variant is present in gnomAD v2.1 and v4.1, with the highest observed South Asian frequency reaching 0.09552% in v4.1 and grpmax filtering allele frequencies of 0.05125% in v2.1 and 0.07930% in v4.1, which are above the PTPN11 RASopathy BA1 threshold of 0.05%.2 No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource.3 Computational evidence does not meet the PTPN11 missense thresholds for either PP3 or BP4: REVEL is 0.301, which is below the PP3 cutoff of 0.7 and just above the BP4 cutoff of 0.3, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.292277.4
Final classification
Benign
BA1BS1BP6
PTPN11
c.53A>G
p.Asn18Ser
This variant
The PTPN11 c.53A>G (p.Asn18Ser) variant has not been observed in COSMIC and has been reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel, with additional benign and likely benign clinical laboratory submissions.
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, BS1 strong benign, BP6 supporting benign; maps to Benign.
Classification rationale
BA1BS1BP6
Benign
PTPN11 c.53A>G
BA1 + BS1 + BP6
→
Benign
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
cspec ↗revelspliceai ↗bayesdel
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 · 16 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
BA1
stand-alone
review
Benign
This variant meets the benign stand-alone population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BA1 threshold of 0.05%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above the same threshold.
gnomAD v4.1 South Asian AF 0.09552% and grpmax FAF 0.07930%gnomAD v2.1 grpmax FAF 0.05125%
BS1
strong
review
Benign
This variant exceeds the BS1 population threshold. In gnomAD v4.1, the highest observed population frequency is 0.09552% in South Asian individuals and the grpmax filtering allele frequency is 0.07930%, both above the BS1 threshold of 0.025%; gnomAD v2.1 also shows a grpmax filtering allele frequency of 0.05125%, above this threshold.
gnomAD v4.1 South Asian AF 0.09552% and grpmax FAF 0.07930%gnomAD v2.1 grpmax FAF 0.05125%
Assessed · not applied
· 7 not met · 9 not assessed
Pathogenic
PS1
No evidence was identified that this amino acid change matches a previously established pathogenic PTPN11 variant; the available ClinVar record for this change is benign by the ClinGen RASopathy expert panel.
PS2
No confirmed de novo occurrence with the case-level details needed for RASopathy point scoring was identified.
PS3
No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource, so functional evidence supporting a damaging effect was not established for PS3.
PS4
No validated count of unrelated affected individuals or case-enrichment point total was identified, and the observed population frequency argues against applying PS4 from the currently available evidence.
PM1
Residue 18 is not listed among the PTPN11 residues allowed for PM1 in the RASopathy specification, and no hotspot evidence supporting this residue was identified.
PM2
This variant is present in population databases, so it is not absent from controls and does not meet PM2_Supporting.
PM5
No pathogenic or likely pathogenic missense comparator at the same residue was identified, so the available evidence does not support PM5 for codon 18.
PM6
No assumed de novo observation with sufficient case-level detail was identified for PM6 scoring.
PP1
No segregation data with informative meioses were identified for this variant.
PP2
The PTPN11 missense z-score needed for PP2 was not identified in the available evidence, so PP2 could not be adjudicated from the reviewed materials.
PP3
Computational evidence does not meet the PTPN11 PP3 threshold: REVEL is 0.301, which is below the required threshold of at least 0.7, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
Benign
BS2
Although this variant is present in gnomAD, the evidence reviewed did not establish the number and clinical status of unaffected individuals needed for BS2 point assignment.
BS4
No informative non-segregation data were identified for this variant.
BP2
No phase or alternate molecular diagnosis data were identified to support BP2 point scoring.
BP4
Computational evidence does not meet the PTPN11 BP4 threshold because REVEL is 0.301, which is above the benign cutoff of 0.3.
BP5
No alternate molecular explanation or benign point total was identified to support BP5 scoring.
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
This variant is present in gnomAD v4.1 (AF= 5.57597e-05; MAF= 0.00558%, 90/1614070 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000955183; MAF= 0.09552%, 87/91082 alleles, homozygotes = 1); grpmax FAF= 0.00079302.
v2.1
This variant is present in gnomAD v2.1 (AF= 9.54464e-05; MAF= 0.00954%, 24/251450 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000751241; MAF= 0.07512%, 23/30616 alleles, homozygotes = 0); grpmax FAF= 0.00051247.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0056%
· 90 / 1,614,070
1 hom · FAF 0.079%
1 hom · FAF 0.079%
South Asian 87 / 91,082 |
0.096% 1 hom |
Remaining individuals 3 / 62,498 |
0.0048% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0095%
· 24 / 251,450
0 hom · FAF 0.051%
0 hom · FAF 0.051%
South Asian 23 / 30,616 |
0.075% |
Remaining individuals 1 / 6,136 |
0.016% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 135112)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.301. BayesDel score = -0.292277.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
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
24728327 ↗
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.
CLINVAR
25173338 ↗
2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR