Variant classification summary

NM_001330437.1:c.127C>T

PTPN11 · NP_001317366.1:p.(Leu43Phe) · NM_001330437.1

GRCh37: chr12:112884192 C>T · GRCh38: chr12:112446388 C>T

Gene: PTPN11 Transcript: NM_001330437.1

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Leu43Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PTPN11 c.127C>T (p.(Leu43Phe), p.(L43F)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with four submissions classified as uncertain significance and one submission classified as likely pathogenic.

2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports PM2 at supporting strength under the PTPN11 RASopathy specification.

3

Available approved functional-study materials did not provide a variant-specific functional result for p.(Leu43Phe), so PS3 could not be applied from the retrieved evidence.

4

Computational evidence supports a damaging missense effect, with REVEL 0.924 above the PP3 threshold of 0.7, BayesDel 0.57613 in a damaging range, and SpliceAI showing no predicted splice effect with a maximum delta score of 0.00.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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. The generic PVS1 assessment also indicates that this variant does not fall into a nonsense, frameshift, or canonical splice-site null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No verified evidence was identified showing that this exact amino acid change, p.(Leu43Phe), has previously been established as pathogenic from a different nucleotide change, so PS1 cannot be applied from the retrieved evidence.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with documented maternity and paternity was identified for this variant, so PS2 cannot be applied from the retrieved evidence.	cspec clinvar
PS3	Not assessed	Approved functional assay frameworks are available for PTPN11, but no variant-specific result for p.(Leu43Phe) was identified in the retrieved approved functional-study materials, so PS3 cannot be applied from the available evidence.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies oncokb
PS4	Not assessed	This variant has been reported in ClinVar, but the retrieved evidence does not provide a verified count of independent affected probands or a case-control enrichment analysis needed for PS4 under the RASopathy specification.	cspec clinvar PMID:15940693 PMID:16358218 PMID:16892325 PMID:18260110 PMID:22781091
PM1	Not met	The PTPN11 RASopathy specification limits PM1 to specific residues and residue ranges involved in the N-SH2/PTP interface, and codon 43 is not included in that defined PM1 residue set. Available hotspot resources also did not show a statistically significant hotspot at this residue.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1. Under the PTPN11 RASopathy specification, absence from controls meets PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in the PTPN11 RASopathy specification.	cspec
PM4	N/A	This is a missense substitution rather than an in-frame insertion, in-frame deletion, or stop-loss variant, so PM4 does not apply.	cspec
PM5	Not assessed	No verified evidence was identified showing a different pathogenic or likely pathogenic missense change at codon 43 that would satisfy the PTPN11 PM5 rule, so PM5 cannot be applied from the retrieved evidence.	cspec clinvar
PM6	Not assessed	No de novo report without full parental confirmation was identified for this variant in the retrieved evidence, so PM6 cannot be applied.	cspec clinvar
PP1	Not assessed	No segregation data or informative meiosis count was identified for this variant, so PP1 cannot be applied.	cspec clinvar
PP2	Not assessed	The PTPN11 specification allows PP2 when the gene missense z score is greater than 3.09, but no gene-level missense z score was identified in the retrieved case files, so PP2 was not assessed.	cspec
PP3	Met	For this missense variant, REVEL is 0.924, which is above the PTPN11 RASopathy PP3 threshold of 0.7. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, supporting a missense rather than splice mechanism, and BayesDel is also in a damaging range at 0.57613. This supports PP3 at supporting strength.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in the PTPN11 RASopathy specification.	cspec
PP5	N/A	PP5 is not applicable in the PTPN11 RASopathy specification.	cspec
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BA1 stand-alone benign threshold of 0.05%, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the BS1 strong benign threshold of 0.025%, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped unaffected individuals, so BS2 was not assessed.	cspec
BS3	N/A	BS3 is not applicable in the PTPN11 RASopathy specification.	cspec
BS4	Not assessed	No nonsegregation data were identified for this variant, so BS4 cannot be applied.	cspec clinvar
BP1	N/A	BP1 in the PTPN11 RASopathy specification is intended for truncating variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply.	cspec
BP2	Not assessed	No phase data or alternative molecular diagnosis evidence was identified for this variant, so BP2 was not assessed.	cspec
BP3	N/A	BP3 is not applicable in the PTPN11 RASopathy specification.	cspec
BP4	Not met	For missense variants, the PTPN11 RASopathy BP4 rule requires REVEL at or below 0.3. The observed REVEL score is 0.924, which is above that threshold. SpliceAI predicts no splice effect with a maximum delta score of 0.00, but this does not overcome the high missense pathogenicity prediction, so BP4 is not met.	cspec revel spliceai bayesdel
BP5	Not assessed	No evidence was identified showing that the phenotype is fully explained by an alternate molecular finding, so BP5 was not assessed.	cspec
BP6	N/A	BP6 is not applicable in the PTPN11 RASopathy specification.	cspec
BP7	N/A	This is a missense variant rather than a synonymous, intronic, or non-coding variant, so BP7 does not apply.	cspec spliceai

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