NM_001330437.1:c.782T>A

PTPN11 · NP_001317366.1:p.(Leu261His) · NM_001330437.1

GRCh37: chr12:112910773 T>A · GRCh38: chr12:112472969 T>A

Gene: PTPN11 Transcript: NM_001330437.1

Final call

Likely Pathogenic

PS4 strong PM1 moderate PM2 supporting PP2 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Leu261His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTPN11 c.782T>A (p.Leu261His) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen RASopathy expert panel classified it as likely pathogenic and documented 7 independent affected occurrences supporting PS4.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting the PTPN11 RASopathy PM2_Supporting threshold for absence from controls.

In a published functional study, codon 261/262/265 substitutions increased MAPK pathway signaling, and codon 261 substitutions were described as moderately activating with altered substrate specificity; however, the available assay evidence for this variant did not meet approved RASopathy VCEP PS3 requirements.

Computational evidence is mixed: REVEL is 0.558, which is below the VCEP PP3 threshold of 0.7 and above the BP4 threshold of 0.3, while SpliceAI predicts no splice impact with a maximum delta score of 0.00.

Final determination: Rule11 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 Likely Pathogenic.

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 reviewed PVS1 assessments indicate that it does not fall into a null-variant category for PVS1 application.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	No independently verified evidence was identified showing the same PTPN11 p.(Leu261His) amino acid change from a different nucleotide substitution.	cspec clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant in the reviewed evidence.	clinvar
PS3	Not met	Published functional work on codon 261 changes showed MAPK pathway activation and altered phosphatase behavior, but the ClinGen RASopathy expert-panel submission states that the assay evidence for this variant did not meet approved PS3 requirements.	clinvar PMID:28074573 vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4	Met	This variant has been reported in 7 independent occurrences in individuals with clinical features of a RASopathy, which supports case enrichment under the expert-panel framework.	clinvar PMID:22253195 PMID:23756559 PMID:28074573
PM1	Met	Residue Leu261 is explicitly listed in the PTPN11 RASopathy specification as a directly interacting N-SH2/PTP interface residue within a critical and well-established functional region, supporting PM1.	cspec clinvar
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 in the reviewed population data, meeting the RASopathy VCEP PM2 threshold for absence from controls.	gnomad_v2 gnomad_v4 cspec clinvar
PM3	N/A	PM3 is not applicable because this variant is being evaluated in an autosomal dominant RASopathy framework rather than a recessive disease setting.	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 assessed	Other disease-associated changes affecting codon 261 have been mentioned in submitter-level evidence, but an independently verified same-codon pathogenic missense comparator suitable for formal PM5 scoring was not fully established from the reviewed sources.	cspec clinvar PMID:28074573
PM6	Not assessed	No assumed de novo occurrence lacking full parentage confirmation was clearly documented for this variant in the reviewed evidence.	clinvar
PP1	Not assessed	One submitter noted segregation with disease in related individuals, but the reviewed evidence did not provide the number of informative meioses needed for formal PP1 scoring.	clinvar
PP2	Met	This is a missense variant in PTPN11, a gene/disease setting for which the RASopathy expert panel has identified missense variation as a common pathogenic mechanism and has applied PP2 to this variant.	cspec clinvar
PP3	Not met	REVEL is 0.558, which is below the PTPN11 RASopathy PP3 threshold of 0.7, and SpliceAI predicts no splice impact with a maximum delta score of 0.00. BayesDel is 0.370262, but this score does not override the VCEP REVEL rule.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not used in this PTPN11 RASopathy VCEP framework for this review.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the BA1 threshold of at least 0.05%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the BS1 threshold of at least 0.025%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing this variant in healthy individuals in a manner sufficient for BS2 scoring.	clinvar gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applied in this PTPN11 RASopathy VCEP framework for this review.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	No non-segregation evidence was identified for this variant.	clinvar
BP1	N/A	This is a missense variant, whereas the RASopathy-specific BP1 guidance is directed to truncating variants in genes without established loss-of-function disease correlation.	cspec
BP2	Not assessed	No phased co-occurrence data were identified that would support BP2 scoring.	clinvar
BP3	N/A	BP3 is not applicable in this PTPN11 RASopathy framework.	cspec
BP4	Not met	REVEL is 0.558, which is above the BP4 threshold of 0.3, so benign computational evidence is not met. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the missense predictor threshold for BP4 is not satisfied.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternate molecular explanation or negative-point evidence set was identified that would support BP5 scoring.	clinvar
BP6	N/A	BP6 is not applied in this framework.	cspec
BP7	N/A	This is not a synonymous, intronic, or non-coding variant, so BP7 does not apply.	cspec spliceai

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