Starting

Initialising…

PTPN11

Final classification

Likely Pathogenic

PTPN11 c.1542G>C · p.Gln514His

PTPN11

Gene

PTPN11

Transcript

NM_001330437.1

HGVS · transcript:coding

NM_001330437.1:c.1542G>C

Consequence

N/A

GRCh38

chr12:112489106 G>C

GRCh37

chr12:112926910 G>C

Basis ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PS1 strong, PM2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic. ▾

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PS1 strong, PM2 supporting, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.

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 ↗

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

PTPN11 NM_001330437.1

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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