Classification rationale

PS1PM2PP3PP5 Likely Pathogenic

PTPN11 c.1542G>C

The PTPN11 c.1542G>C (p.Gln514His) variant has been observed in somatic cancers in COSMIC (8 occurrences) and has been reported in ClinVar as pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls.² ClinVar also documents a different nucleotide change producing the same amino acid substitution, supporting PS1, and in silico results support a deleterious missense effect with REVEL 0.94 above the RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.563665, and no predicted splice impact by SpliceAI (max delta score 0.00).³

PS1 + PM2 + PP3 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 clinvar ↗cspec ↗revelbayesdelspliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001330437.1 · variants mapped to exon structure

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 15 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PS1 strong review Pathogenic

ClinVar shows that the same amino acid substitution in PTPN11, p.Gln510His corresponding to this transcript's p.Gln514His, has also been established as pathogenic from a different nucleotide change. SpliceAI predicts no splice effect for this variant (max delta score 0.00), supporting interpretation at the protein level rather than through altered splicing.

Current variant corresponds to PTPN11 p.Gln510His / p.(Q514H)ClinVar also contains a pathogenic alternate nucleotide change producing the same amino acid substitutionSpliceAI max delta score 0.00

clinvar ↗spliceai ↗cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, satisfying the PTPN11 RASopathy PM2 requirement that the variant be absent from population controls.

gnomAD v2.1 absentgnomAD v4.1 absent

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP3 supporting review Pathogenic

For missense variants, the PTPN11 RASopathy specification supports PP3 when REVEL is at least 0.7. This variant has REVEL 0.94, which is above the 0.7 threshold; BayesDel is 0.563665, also supporting a deleterious effect, and SpliceAI predicts no significant splice impact with a max delta score of 0.00.

REVEL 0.94BayesDel 0.563665SpliceAI max delta 0.00

cspec ↗spliceai ↗

PP5 supporting review Pathogenic

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.

PTPN11 CSPEC/VCEP lists PP5 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 11 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant in the reviewed evidence, so PS2 was not applied.

PS3 RASopathy VCEP-approved functional assay frameworks for PTPN11 were reviewed, but no variant-specific approved functional result for p.(Gln514His) was identified in the reviewed materials.

PS4 This variant has been reported in ClinVar and is classified there as pathogenic by an expert panel, but the reviewed sources did not provide the point-based affected-proband counts required to apply the RASopathy VCEP PS4 rule for this exact variant.

PM1 The PTPN11 RASopathy specification restricts PM1 to listed critical residues in the N-SH2/PTP interaction interface, and residue 514 is not included in that list.

PM5 Other pathogenic missense changes have been reported at the homologous canonical residue, including Gln510Arg and Gln510Glu, which corresponds to this transcript region.

PM6 No presumed de novo report without full parental confirmation was identified for this variant in the reviewed evidence, so PM6 was not applied.

PP1 No segregation data with informative meioses were identified for this variant, so PP1 was not applied.

PP2 The PTPN11 RASopathy framework allows PP2 when the gnomAD missense z score is greater than 3.09, but a gene-level missense z score was not documented in the reviewed case materials.

Benign

BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below the BA1 stand-alone benign threshold of 0.05% population frequency.

BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not meet the BS1 benign strong threshold of 0.025% population frequency.

BS2 No evidence was identified showing this variant in a sufficient number of unaffected individuals, so BS2 was not applied.

BS4 No nonsegregation data were identified for this variant, so BS4 was not applied.

BP2 No evidence was identified showing this variant in trans with a pathogenic variant for a fully explained phenotype or in a context that would support BP2, so BP2 was not applied.

BP4 The PTPN11 RASopathy specification supports BP4 for missense variants only when REVEL is 0.3 or lower.

BP5 No evidence was identified for an alternate molecular explanation that would account for the phenotype independently of this variant, so BP5 was not applied.

N/A · 9 PVS1 · PM3 · PM4 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.94. BayesDel score = 0.563665.

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61005626, n = 8 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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