NM_001330437.1:c.188A>G

PTPN11 · NP_001317366.1:p.(Tyr63Cys) · NM_001330437.1

GRCh37: chr12:112888172 A>G · GRCh38: chr12:112450368 A>G

Gene: PTPN11 Transcript: NM_001330437.1

Final call

VUS

PS3 supporting PP3 supporting PP5 supporting

Variant details

Gene

PTPN11

Transcript

NM_001330437.1

Protein

NP_001317366.1:p.(Tyr63Cys)

gnomAD AF

8.678704443000749e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTPN11 c.188A>G (p.Tyr63Cys) variant has been reported in ClinVar as pathogenic, including an expert panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.

This variant is present at very low frequency in gnomAD, with AF 0.00120% in v2.1 and AF 0.00087% in v4.1, which is below the RASopathy BA1 and BS1 thresholds but does not meet the PTPN11 VCEP requirement for PM2 because the variant is not absent from controls.

In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, and the RASopathy VCEP lists this assay type as an approved functional assay for PTPN11, supporting a gain-of-function effect.

Computational evidence supports a deleterious missense effect, with REVEL 0.955 above the PTPN11 VCEP PP3 threshold of 0.7, BayesDel 0.482421, and SpliceAI showing no significant splice impact with a maximum delta score of 0.03.

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 scaffold also indicates that this variant does not fall into a null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant producing the same p.Tyr63Cys amino acid change by a different nucleotide substitution was identified, so PS1 is not met.	clinvar cspec
PS2	Not assessed	Published reports document de novo PTPN11 variants in Noonan syndrome cohorts, but the available evidence reviewed here does not confirm p.Tyr63Cys as de novo with the parentage information required to assign PS2.	PMID:12325025 PMID:15928039 cspec
PS3	Met	In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, consistent with a gain-of-function effect. The RASopathy VCEP lists SHP-2 phosphatase activity as an approved PTPN11 assay, supporting PS3 at the supporting level.	PMID:15834506 vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PS4	Not assessed	This variant has been reported in affected individuals with Noonan syndrome, including one report identifying Tyr63Cys among seven mutation-positive Japanese cases and another reporting Tyr63Cys in two unrelated families. However, the available evidence did not provide the point-based proband scoring details needed to assign a PS4 strength under the RASopathy VCEP framework.	PMID:12161469 PMID:12325025 clinvar cspec
PM1	N/A	Residue 63 lies within the N-SH2/PTP interaction interface listed in the PTPN11 specification, but the RASopathy VCEP states that PM1 is not applied to specific amino acid residues and directs residue-based evidence to PM5 instead. Because no qualifying same-codon comparator was established, PM1 was not applied.	cspec pm5_candidates
PM2	Not met	This variant is present in gnomAD, with AF 0.00120% in v2.1 (3/251010 alleles) and AF 0.00087% in v4.1 (14/1613144 alleles). Because the PTPN11 RASopathy specification requires absence from controls for PM2, PM2 is not met.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is not applicable in the PTPN11 RASopathy specification.	cspec
PM4	N/A	This is a missense variant and does not cause an in-frame protein length change or stop-loss event, so PM4 is not applicable.	cspec
PM5	Not met	No qualifying different pathogenic or likely pathogenic missense change at the same codon was identified for application of PM5. The current variant itself cannot be used as its own same-codon comparator.	pm5_candidates cspec clinvar
PM6	Not assessed	The available evidence did not document p.Tyr63Cys as assumed de novo without full parentage confirmation, so PM6 was not assigned.	PMID:12325025 PMID:15928039 cspec
PP1	Not assessed	No segregation data with enough informative meioses were identified for p.Tyr63Cys, so PP1 was not assigned.	PMID:12161469 PMID:12325025 cspec
PP2	Not assessed	The PTPN11 specification allows PP2 when the gene missense z score is greater than 3.09, but the reviewed evidence did not provide the gene-level z score needed to confirm PP2 here.	cspec
PP3	Met	Computational evidence supports a deleterious effect. REVEL is 0.955, which is above the PTPN11 VCEP PP3 threshold of 0.7; BayesDel is 0.482421; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting a missense rather than splice-driven interpretation.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable in the PTPN11 RASopathy specification.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency is below the BA1 threshold. The highest observed subpopulation frequency is 0.00544% in gnomAD v2.1 East Asian and 0.00223% in gnomAD v4.1 East Asian, both below the RASopathy BA1 threshold of 0.05%.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Population frequency is below the BS1 threshold. The highest observed subpopulation frequency is 0.00544% in gnomAD v2.1 East Asian and 0.00223% in gnomAD v4.1 East Asian, both below the RASopathy BS1 threshold of 0.025%.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	The available evidence does not show this variant in the number and context of unaffected individuals required for BS2 under the RASopathy specification.	cspec gnomad_v2 gnomad_v4
BS3	N/A	BS3 is not applicable in the PTPN11 RASopathy specification.	cspec
BS4	Not assessed	No non-segregation evidence for p.Tyr63Cys was identified, so BS4 was not assigned.	PMID:12161469 PMID:12325025 cspec
BP1	N/A	This is a missense variant. In the RASopathy specification, BP1 is used for truncating variants in genes without an established loss-of-function disease correlation, so BP1 is not applicable here.	cspec
BP2	Not assessed	No phase data or alternate pathogenic molecular explanation was identified to support BP2.	cspec
BP3	N/A	BP3 is not applicable in the PTPN11 RASopathy specification.	cspec
BP4	Not met	Computational evidence does not support BP4. REVEL is 0.955, which is well above the benign BP4 threshold of 0.3, and BayesDel is positive rather than reassuring. SpliceAI predicts no significant splice impact, but this does not overcome the deleterious missense prediction profile.	revel bayesdel spliceai cspec
BP5	Not assessed	No alternate molecular diagnosis or independent cause sufficient to support BP5 was identified.	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 change, so BP7 is not applicable.	cspec spliceai

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