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
PTPN11
Final classification
Benign
PTPN11 c.53A>G · p.Asn18Ser
PTPN11
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
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 · 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