PTPN11c.1508G>TPathogenic

Print report

Variant interpretation report

PTPN11 c.1508G>T, p.(Gly503Val)

NM_002834.4:c.1508G>T NP_002825.3:p.(Gly503Val) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PTPN11

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 2 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen PTPN11 VCEP v1.0
Other laboratories (ClinVar): 1 other
Pipeline record: 31 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PS3 (strong): SHP-2 phosphatase activity assay (VCEP-approved gene-specific functional assay) demonstrated 1.4-fold increased phosphatase activity for G503V compared to wild-type SHP-2 in COS7 cells, consistent with gain-of-function mechanism of RASopathy.
PM1 (moderate): Variant is located at codon 503 in the PTP catalytic domain of SHP-2, a critical functional domain. Residue is within a statistically significant hotspot; adjacent residues S502 and M504 are listed as pathogenic validation controls in the VCEP functional studies spreadsheet.
PM2 (moderate): Variant is completely absent from all population databases per VCEP requirement (gnomAD v2.1, v4.1, and gnomAD-Canada).
PP2 (supporting): VCEP specifies PP2 is applicable to all RASopathy genes described and curated. PTPN11 is a RASopathy gene with a low rate of benign missense variation and missense variants are a common disease mechanism.
PP3 (supporting): Multiple lines of computational evidence support a deleterious effect: REVEL score 0.989 (highly deleterious), BayesDel score 0.608, statistically significant hotspot at this residue. SpliceAI predicts no splice impact (max delta 0.19) and does not contribute to PP3.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen PTPN11 VCEP v1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 5 Benign evidence criteria: 0

Pathogenic criteria applied · 5

PS3Strong

PS3 · strong

SHP-2 phosphatase activity assay (VCEP-approved gene-specific functional assay) demonstrated 1.4-fold increased phosphatase activity for G503V compared to wild-type SHP-2 in COS7 cells, consistent with gain-of-function mechanism of RASopathy.

PM1Moderate

PM1 · moderate

Variant is located at codon 503 in the PTP catalytic domain of SHP-2, a critical functional domain. Residue is within a statistically significant hotspot; adjacent residues S502 and M504 are listed as pathogenic validation controls in the VCEP functional studies spreadsheet.

PM2Moderate

PM2 · moderate

Variant is completely absent from all population databases per VCEP requirement (gnomAD v2.1, v4.1, and gnomAD-Canada).

PP2Supporting

PP2 · supporting

VCEP specifies PP2 is applicable to all RASopathy genes described and curated. PTPN11 is a RASopathy gene with a low rate of benign missense variation and missense variants are a common disease mechanism.

PP3Supporting

PP3 · supporting

Multiple lines of computational evidence support a deleterious effect: REVEL score 0.989 (highly deleterious), BayesDel score 0.608, statistically significant hotspot at this residue. SpliceAI predicts no splice impact (max delta 0.19) and does not contribute to PP3.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 moderate, PP2 supporting, PP3 supporting; combination = 1 strong + 2 moderate + 2 supporting, which maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.190 maximum delta

Recorded SpliceAI maximum delta score: 0.190. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 other. ClinVar API review status: no assertion criteria provided.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTPN11 VCEP v1.0, with the data and sources behind each one.

26 criteria with recorded statuses: 5 met · 14 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_002834.4:c.1508G>T (p.Gly503Val) in PTPN11 is a missense variant in the PTP catalytic domain of SHP-2, located within a statistically significant hotspot.

This variant is completely absent from population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2).

Functional studies using a VCEP-approved SHP-2 phosphatase activity assay demonstrated 1.4-fold increased catalytic activity for G503V compared to wild-type, consistent with the gain-of-function mechanism of RASopathies (PS3).

The variant resides in the PTP catalytic domain at a residue adjacent to known pathogenic variants (S502, M504) and within a mutational hotspot (PM1).

PP2 applies per VCEP specification as PTPN11 is a RASopathy gene with missense variants as a common disease mechanism.

Multiple computational tools predict a deleterious effect: REVEL score 0.989, BayesDel score 0.608, supporting PP3.

PS3 was applied at strong per VCEP specifications; the variant was directly tested in an approved SHP-2 phosphatase assay and showed increased activity. Modest activation (1.4-fold) compared to other pathogenic PTPN11 variants noted but does not preclude application per VCEP rules.

Met · 5

PS3 StrongSHP-2 phosphatase activity assay (VCEP-approved gene-specific functional assay) demonstrated 1.4-fold increased phosphatase activity for G503V compared to wild-type SHP-2 in COS7 cells, consistent with gain-of-function mechanism of RASopathy. Details ▾Hide ▴

Evidence considered

Niihori et al. (2005) directly tested G503V in immune complex phosphatase assay
SHP-2 Phosphatase Activity assay is an approved VCEP functional study (gene-specific for PTPN11) at the Strong level.

Still missing

1.4-fold activation is modest compared to other NS/JMML mutations (6-12x)
variant identified in somatic JMML context
not germline NS.

Sources

PMID:15834506 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies

PM1 ModerateVariant is located at codon 503 in the PTP catalytic domain of SHP-2, a critical functional domain. Residue is within a statistically significant hotspot; adjacent residues S502 and M504 are listed as pathogenic validation controls in the VCEP functional studies spreadsheet. Details ▾Hide ▴

Evidence considered

Cancerhotspots.org identifies residue as a statistically significant hotspot. VCEP SHP-2 Phosphatase Activity assay lists S502T and M504V as P/LP validation controls
confirming domain-level functional significance.

Sources

vcep_svi_rasopathy_vcep_v2_approved_functional_studies

PM2 ModerateVariant is completely absent from all population databases per VCEP requirement (gnomAD v2.1, v4.1, and gnomAD-Canada). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes). Absent from gnomAD v4.1. Absent from gnomAD-Canada v1.0.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP2 SupportingVCEP specifies PP2 is applicable to all RASopathy genes described and curated. PTPN11 is a RASopathy gene with a low rate of benign missense variation and missense variants are a common disease mechanism. Details ▾Hide ▴

Evidence considered

VCEP criteria: 'PP2 is applicable to all RASopathy genes described and curated herein.'

Sources

cspec ↗

PP3 SupportingMultiple lines of computational evidence support a deleterious effect: REVEL score 0.989 (highly deleterious), BayesDel score 0.608, statistically significant hotspot at this residue. SpliceAI predicts no splice impact (max delta 0.19) and does not contribute to PP3. Details ▾Hide ▴

Evidence considered

REVEL 0.989 strongly predicts deleterious effect. BayesDel 0.608 supports deleterious prediction. Residue is a statistically significant hotspot. SpliceAI delta 0.19 is not contributory.

Sources

revelbayesdelspliceai ↗

Not met · 14 · evaluated, threshold not reached

PS1 No previously established pathogenic variant with the identical amino acid change (p.Gly503Val) has been classified as pathogenic per VCEP criteria in a germline RASopathy context. Details ▾Hide ▴

Evidence considered

ClinVar variation 40560 reports classification 'other' with a single submitter. G503V has only been reported as a somatic JMML finding (Niihori 2005)
not as a germline pathogenic variant.

Sources

clinvar ↗PMID:15834506 ↗

PS2 No de novo occurrence with confirmed parentage has been reported for this variant. Details ▾Hide ▴

Evidence considered

No de novo data identified in any source.

PS4 No independent occurrences meeting VCEP proband-counting thresholds (>=1 for supporting, >=3 for moderate, >=5 for strong) are available. ClinVar contains only one submission with classification 'other' in a somatic context. Details ▾Hide ▴

Evidence considered

ClinVar variation 40560: single submitter
classification 'other'. Parsons et al. (26822237) and Martinelli et al. (19681119) do not mention G503V in abstract or full text.

Still missing

No germline proband data available.

Sources

clinvar ↗PMID:26822237 ↗PMID:19681119 ↗

PM5 No pathogenic missense variant at codon 503 has been established per VCEP criteria. Despite the variant being a missense change (G503V), no comparator pathogenic variant at this residue exists in ClinVar or the literature. Details ▾Hide ▴

Evidence considered

No other missense changes at codon 503 have been reported or classified as pathogenic. Adjacent residues S502 and M504 have pathogenic variants
but PM5 requires a different missense at the same residue.

PM6 No confirmed de novo occurrence has been reported for this variant. Details ▾Hide ▴

Evidence considered

No de novo data identified.

PP1 No cosegregation data available. VCEP requires at least three informative meioses for PP1 at supporting level. Details ▾Hide ▴

Evidence considered

No segregation data identified.

Still missing

No family data available.

BA1 Allele frequency is 0% in gnomAD, well below the VCEP-approved BA1 threshold of >=0.05%. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD v2.1 and v4.1 (AF = 0.0).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Allele frequency is 0% in gnomAD, well below the VCEP-approved BS1 threshold of >=0.025%. Details ▾Hide ▴

Evidence considered

Variant is absent from gnomAD v2.1 and v4.1 (AF = 0.0).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 VCEP requires well-phenotyped family members (>3 instances) for BS2 application; no such data available. General population data cannot substitute. Details ▾Hide ▴

Evidence considered

No well-phenotyped healthy adult carriers identified.

Still missing

No family phenotype data available.

BS3 Functional data demonstrates increased SHP-2 phosphatase activity (1.4-fold, gain-of-function), inconsistent with a benign effect on protein function. BS3 requires functional studies showing no damaging effect; the available data supports pathogenicity. Details ▾Hide ▴

Evidence considered

Niihori et al. (2005) showed 1.4-fold increased phosphatase activity for G503V
supporting a damaging gain-of-function effect rather than a benign effect.

Sources

PMID:15834506 ↗

BS4 No segregation data available for this variant. Details ▾Hide ▴

Evidence considered

No family studies or segregation data identified.

Still missing

No family data available.

BP2 No evidence of the variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴

Evidence considered

No phase data identified.

BP4 Computational evidence does not suggest no impact on gene product. REVEL 0.989 strongly predicts deleterious effect, BayesDel 0.608 is borderline-deleterious, and the residue is a statistically significant hotspot. These findings contradict BP4 and instead support PP3. Details ▾Hide ▴

Evidence considered

REVEL 0.989 strongly predicts a damaging effect on protein function. Multiple in silico tools indicate deleterious impact
inconsistent with BP4.

Sources

revelbayesdel

BP5 No alternate molecular basis for disease has been identified in a case harboring this variant. Details ▾Hide ▴

Evidence considered

No case with an alternate molecular diagnosis identified.

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 VCEPPVS1 is not applicable per ClinGen RASopathy VCEP v1.0; loss-of-function has not been clearly established as a disease mechanism for RASopathies and this is a missense variant. Details ▾Hide ▴

Evidence considered

VCEP explicitly designates PVS1 as Not Applicable.

Sources

cspec ↗

PP4 VCEPVCEP explicitly states this criterion is not applicable to the RASopathies; proband counting is handled via PS4. Details ▾Hide ▴

Evidence considered

VCEP: 'This criterion is not applicable to the RASopathies. See PS4 criterion for proband counting options.'

Sources

cspec ↗

PP5 VCEPVCEP explicitly states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Evidence considered

VCEP: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'

Sources

cspec ↗

BP1 N/ABP1 per VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, exon/gene deletions) in RASopathy genes without established LOF correlation. This is a missense variant. Details ▾Hide ▴

Evidence considered

VCEP BP1 is specifically for truncating variants. PTPN11 G503V is a missense substitution.

Sources

cspec ↗

BP6 VCEPVCEP explicitly states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴

Evidence considered

VCEP: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'

Sources

cspec ↗

BP7 N/ABP7 applies to synonymous (silent) variants and intronic/non-coding variants. This is a missense variant (p.Gly503Val). Details ▾Hide ▴

Evidence considered

Variant is a missense substitution (c.1508G>T
p.Gly503Val)
not a synonymous variant.

PS5 N/APS5 is not defined in the ClinGen RASopathy VCEP v1.0 criteria. Details ▾Hide ▴

Evidence considered

PS5 is absent from the VCEP criteria.json
not specified for use.

Sources

cspec ↗

Identifiers

Gene: PTPN11
Transcript: NM_002834.4
Coding (HGVS c.): NM_002834.4:c.1508G>T
Protein (HGVS p.): NP_002825.3:p.(Gly503Val)
GRCh38: chr12:112489084 G>T
GRCh37: chr12:112926888 G>T
ClinVar: 40560

Gene diagram

Every interpreted variant in PTPN11, mapped onto the exon structure of NM_002834.4. Select a row to find it on the plot.

PTPN11NM_002834.4

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in PTPN11 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +286 bp

0.000

SpliceAI acceptor gainat -94 bp

0.000

SpliceAI donor lossat +91 bp

0.000

SpliceAI donor gainat -6 bp

0.190

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.070

Other predictors

REVEL: 0.989
BayesDel: 0.608

How the predictions were used

Evidence considered

REVEL 0.989 strongly predicts deleterious effect. BayesDel 0.608 supports deleterious prediction. Residue is a statistically significant hotspot. SpliceAI delta 0.19 is not contributory.

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL 0.989 strongly predicts a damaging effect on protein function. Multiple in silico tools indicate deleterious impact
inconsistent with BP4.

Sources

revelbayesdel

BP7 N/ABP7 applies to synonymous (silent) variants and intronic/non-coding variants. This is a missense variant (p.Gly503Val). Details ▾Hide ▴

Evidence considered

Variant is a missense substitution (c.1508G>T
p.Gly503Val)
not a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.989. BayesDel score = 0.607986.

6 paper records listed. 1 cited in the classification.

Cited in the classification

Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.

Niihori T et al. · 2005

G503V (c.1508G>T) was identified as a novel somatic mutation in a JMML bone-marrow-derived cell line among 29 pediatric leukemia cases. Immune complex phosphatase assay in COS7 cells demonstrated 1.4-fold increased phosphatase activity compared to wild-type SHP-2, consistent with gain-of-function.
→ PS3 Names this variant
PMID 15834506 ↗
Source detail

The novel G503V (1508G>T) mutation was detected in a bone-marrow-derived cell line from a JMML patient.

Location Results, 'PTPN11 mutation detection and phosphatase assay in childhood leukemia' section

Context Immune complex phosphatase assay; COS7 cells transfected with FLAG-tagged WT or mutant SHP-2 cDNA; Src phosphopeptide substrate; malachite green detection

Other recorded publications

Mutations of the PTPN11 and RAS genes in rhabdomyosarcoma and pediatric hematological malignancies.

Chen Y et al. · 2006

Screened PTPN11 mutations in RMS and pediatric hematological malignancies. Identified A72T, A72V, A72D, D61V, R152H, E76G, G60V, E76K, E76Q, E76V mutations but did not report G503V.
Does not name this variant
PMID 16518851 ↗
Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.

Shern JF et al. · 2014

Comprehensive genomic analysis of 147 rhabdomyosarcoma tumors. PTPN11 mutations were identified in 2 PFN tumors but specific variant identities were not reported. G503V was not mentioned.
Does not name this variant
PMID 24436047 ↗
Quoted passage
Thirty-three genes were found to recurrently harbor expressed mutations including PTPN11 (0 PFP vs. 2 PFN)
PTPN11 mentioned in Results and Figure 5
RAS signaling dysregulation in human embryonal Rhabdomyosarcoma.

Martinelli S et al. · 2009

Investigated RAS signaling dysregulation in embryonal rhabdomyosarcoma. PTPN11 G503V was not mentioned in the abstract; full text not available for review.
Does not name this variant
PMID 19681119 ↗
Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.

Parsons DW et al. · 2016

Reported diagnostic yield of clinical tumor and germline WES for children with solid tumors. PTPN11 G503V was not identified in this paper.
Does not name this variant
PMID 26822237 ↗
Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.

Li MM et al. · 2017

AMP/ASCO/CAP joint consensus guidelines for somatic variant interpretation in cancer. Does not discuss individual PTPN11 variants.
Does not name this variant
PMID 27993330 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.190 Open source ↗

ClinVar 1 other Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as other (1 clinical laboratory). (ClinVarID = 40560)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.989. BayesDel score = 0.607986.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant lies in a statistically significant hotspot.