NM_001330437.1:c.53A>G

PTPN11 · NP_001317366.1:p.(Asn18Ser) · NM_001330437.1

GRCh37: chr12:112884118 A>G · GRCh38: chr12:112446314 A>G

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Benign

BA1 stand-alone benign BS1 strong benign BP6 supporting benign

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Asn18Ser)

gnomAD AF

5.575966345945343e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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%.

No approved variant-specific functional study for p.(Asn18Ser) was identified in the RASopathy VCEP approved functional studies resource.

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.

Final determination: Rule17 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the PTPN11 RASopathy specification marks PVS1 as not applicable for this criterion assessment.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	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.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with the case-level details needed for RASopathy point scoring was identified.	clinvar cspec
PS3	Not met	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.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb cspec
PS4	Not assessed	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.	clinvar gnomad_v2 gnomad_v4 cspec
PM1	Not met	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.	cspec hotspots
PM2	Not met	This variant is present in population databases, so it is not absent from controls and does not meet PM2_Supporting.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable under the PTPN11 RASopathy specification for this evaluation.	cspec
PM4	N/A	This is a missense substitution and does not cause a protein length change, so PM4 does not apply.	cspec
PM5	Not met	No pathogenic or likely pathogenic missense comparator at the same residue was identified, so the available evidence does not support PM5 for codon 18.	clinvar cspec
PM6	Not assessed	No assumed de novo observation with sufficient case-level detail was identified for PM6 scoring.	clinvar cspec
PP1	Not assessed	No segregation data with informative meioses were identified for this variant.	clinvar cspec
PP2	Not assessed	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.	cspec
PP3	Not met	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.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable under the PTPN11 RASopathy specification for this evaluation.	cspec
PP5	N/A	PP5 is not applicable under the PTPN11 RASopathy specification.	cspec
BA1	Met	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_v2 gnomad_v4 cspec
BS1	Met	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_v2 gnomad_v4 cspec
BS2	Not assessed	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.	gnomad_v4 cspec
BS3	N/A	BS3 is not applicable under the PTPN11 RASopathy specification for this evaluation.	cspec
BS4	Not assessed	No informative non-segregation data were identified for this variant.	clinvar cspec
BP1	N/A	BP1 in this framework is intended for truncating variants in genes without established loss-of-function disease correlation; this variant is missense, so BP1 does not apply.	cspec
BP2	Not assessed	No phase or alternate molecular diagnosis data were identified to support BP2 point scoring.	cspec
BP3	N/A	BP3 is not applicable under the PTPN11 RASopathy specification.	cspec
BP4	Not met	Computational evidence does not meet the PTPN11 BP4 threshold because REVEL is 0.301, which is above the benign cutoff of 0.3. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and BayesDel is -0.292277, but the panel's missense BP4 rule is not met.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation or benign point total was identified to support BP5 scoring.	cspec
BP6	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.	cspec clinvar
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 does not apply.	cspec spliceai

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