0%
PTPN11c.200G>AUncertain significance
Print report
Variant interpretation report

PTPN11 c.200G>A, p.(Gly67Glu)

NM_002834.4:c.200G>A NP_002825.3:p.(Gly67Glu) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About PTPN11

No gene-level summary was recorded for this case.

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 v2.3.0. 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting

The variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per RASopathy VCEP specifications, PM2 is downgraded to Supporting strength when the variant is absent from controls.

PP2Supporting
PP2 · supporting

PTPN11 has a gnomAD missense z-score substantially exceeding 3.09, indicating strong constraint against missense variation. Per RASopathy VCEP specifications, a missense z-score >3.09 qualifies for PP2 at Supporting strength.

PP3Supporting
PP3 · supporting

REVEL score is 0.89, which exceeds the RASopathy VCEP threshold of ≥0.7 for PP3 at Supporting strength. Additionally, SpliceAI predicts no significant splice impact (max delta score 0.02), so splicing is not a confounding factor.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting, PP3 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

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

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV109433876, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 15 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002834.4:c.200G>A (p.Gly67Glu) in PTPN11 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada.

PTPN11 has a gnomAD missense z-score >3.09, indicating strong constraint against missense variation and supporting pathogenicity under PP2 at Supporting strength per RASopathy VCEP specifications.

REVEL in silico prediction score is 0.89, exceeding the VCEP threshold of 0.70 for PP3 at Supporting strength, consistent with a deleterious effect on protein function.

The variant does not meet criteria for PS1 (no known pathogenic G67E), PM1 (position 67 is outside the VCEP-defined critical functional domain residue set), PM5 (no pathogenic comparators at codon 67), or any other pathogenic criterion above Supporting strength.

With PM2_Supporting, PP2_Supporting, and PP3_Supporting met (three Supporting-level pathogenic criteria), the variant does not satisfy any Pathogenic or Likely Pathogenic combination rule in the RASopathy VCEP Version 2.3.0 framework. No Likely Pathogenic rule is triggered with fewer than four Supporting criteria in the absence of Moderate or Strong evidence. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 3

PM2 SupportingThe variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per RASopathy VCEP specifications, PM2 is downgraded to Supporting strength when the variant is absent from controls. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP2 SupportingPTPN11 has a gnomAD missense z-score substantially exceeding 3.09, indicating strong constraint against missense variation. Per RASopathy VCEP specifications, a missense z-score >3.09 qualifies for PP2 at Supporting strength. Details ▾Hide ▴
Evidence considered
  • PTPN11 gnomAD missense z-score >3.09
  • consistent with a gene where missense variants are a common disease mechanism and benign missense variation is depleted.
Sources
gnomad_v2 ↗
PP3 SupportingREVEL score is 0.89, which exceeds the RASopathy VCEP threshold of ≥0.7 for PP3 at Supporting strength. Additionally, SpliceAI predicts no significant splice impact (max delta score 0.02), so splicing is not a confounding factor. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.89 (≥0.7 threshold met).
  • SpliceAI max delta 0.02 — no predicted splice alteration.
Sources
revelspliceai ↗

Not met · 15 · evaluated, threshold not reached

PS1 PS1 requires the same amino acid change (p.Gly67Glu) as a previously established pathogenic variant in PTPN11. No pathogenic or likely pathogenic p.Gly67Glu variant was identified in ClinVar or the literature. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for NM_002834.4:c.200G>A or p.Gly67Glu in PTPN11.
Still missing
  • No previously classified pathogenic variant with the same amino acid change is available for comparison.
Sources
clinvar ↗
PS2 PS2 requires de novo occurrence with confirmed maternity and paternity in a patient with a RASopathy phenotype. No de novo reports were identified for this variant in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No de novo observations for NM_002834.4:c.200G>A were identified in any evidence source.
Still missing
  • No proband or family data available to assess de novo status.
PS3 PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect using VCEP-approved assays. The VCEP-approved functional studies spreadsheet was searched and does not include p.Gly67Glu (G67E) among tested variants in any approved assay (RAS Activation, MEK Activation, ERK Activation, or SHP-2 Phosphatase Activity). OncoKB reports no variant-specific reviewed functional evidence. No publications with functional data for this variant were identified. Details ▾Hide ▴
Evidence considered
  • VCEP-approved functional studies spreadsheet contains no G67E entry in any approved assay for PTPN11.
  • OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence.
Still missing
  • No functional data for p.Gly67Glu exists in VCEP-approved assays
  • de novo functional characterization would be required.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesoncokb ↗
PS4 PS4 requires significantly increased prevalence in affected individuals versus controls, assessed via point-based scoring in the RASopathy VCEP. The variant is absent from ClinVar with no reported probands. Zero points are scored. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no proband observations available for case-control comparison.
Still missing
  • No affected individuals reported with this variant.
Sources
clinvar ↗
PM1 PM1 in the RASopathy VCEP for PTPN11 is applicable only to specific directly interacting residues between N-SH2 and PTPN domains: AA 4, 7–9, 58–63, 69–77, 247, 251, 255, 256, 258, 261, 265, 278–281, 284. The variant p.Gly67Glu is at position 67, which lies between the listed ranges (58–63 and 69–77) and is not included in the VCEP-defined functional domain residue set. Details ▾Hide ▴
Evidence considered
  • Position 67 is not among the VCEP-specified critical functional domain residues for PTPN11 PM1 application.
Sources
cspec ↗
PM5 PM5 requires a different pathogenic or likely pathogenic missense change at the same codon (Gly67). No such comparator variants were identified at codon 67 in ClinVar or any evidence source. The automated PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero pathogenic/likely pathogenic variants at codon 67 (Gly67) in PTPN11.
Still missing
  • No known pathogenic variants at codon 67 to serve as PM5 comparator.
Sources
pm5_candidates
PM6 PM6 requires assumed de novo occurrence without confirmation of paternity and maternity. No de novo observations for this variant were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No assumed de novo reports identified for NM_002834.4:c.200G>A.
Still missing
  • No proband data available to assess de novo status.
PP1 PP1 requires co-segregation with disease in multiple affected family members. No family or segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data available.
Still missing
  • No family or segregation information available for this variant.
BA1 BA1 requires a gnomAD filtering allele frequency ≥0.05%. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0. Details ▾Hide ▴
Evidence considered
  • gnomAD filtering allele frequency is 0% (<0.05% threshold).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 BS1 requires a gnomAD filtering allele frequency ≥0.025%. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0. Details ▾Hide ▴
Evidence considered
  • gnomAD filtering allele frequency is 0% (<0.025% threshold).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 BS2 requires observation in healthy adult individuals. The variant is absent from all population databases, with no observations in any individual (affected or unaffected). Details ▾Hide ▴
Evidence considered
  • Variant is absent from gnomAD
  • no healthy adult carriers identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS4 BS4 requires lack of segregation in affected family members. No family or segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data available.
Still missing
  • No family or segregation data available to evaluate BS4.
BP2 BP2 awards points for an alternative molecular cause of a RASopathy in the same gene or in conjunction with BP5. No alternative molecular cause has been identified alongside this variant. Details ▾Hide ▴
Evidence considered
  • No evidence of an alternative molecular cause for disease in any proband carrying this variant.
Still missing
  • No proband data available to assess co-occurring molecular diagnoses.
BP4 BP4 requires REVEL score ≤0.3 for missense variants per RASopathy VCEP specifications. The REVEL score for this variant is 0.89, which does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.89 (>0.3 threshold for BP4).
Sources
revel
BP5 BP5 awards points for an alternative molecular cause of a RASopathy in a different gene when the phenotype is consistent. No alternative molecular cause has been identified. Details ▾Hide ▴
Evidence considered
  • No evidence of an alternative molecular cause for disease.
Still missing
  • No proband data available.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP for PTPN11 Version 2.3.0 declares PVS1 not applicable because loss of function is not an established disease mechanism for RASopathies. Additionally, NM_002834.4:c.200G>A (p.Gly67Glu) is a missense variant, not a null variant. Details ▾Hide ▴
Evidence considered
  • VCEP CSPEC document ID 643243113 declares PVS1 not applicable for PTPN11 RASopathy interpretation.
Sources
cspec ↗
PM3 VCEPPTPN11 RASopathies follow autosomal dominant inheritance; PM3 (detected in trans for recessive disorders) is not applicable per the RASopathy VCEP. Details ▾Hide ▴
Evidence considered
  • VCEP declares PM3 not applicable for PTPN11.
Sources
cspec ↗
PM4 N/APM4 applies to protein length changes (in-frame deletions/insertions, stop-loss). NM_002834.4:c.200G>A is a missense substitution, not a protein-length-altering variant. Details ▾Hide ▴
Evidence considered
  • Variant is a single-nucleotide missense substitution
  • not an in-frame indel or stop-loss.
PP4 VCEPThe RASopathy VCEP declares PP4 not applicable; phenotype specificity is addressed through PS4 point-based scoring instead. Details ▾Hide ▴
Evidence considered
  • VCEP declares PP4 not applicable for PTPN11.
Sources
cspec ↗
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the RASopathy VCEP Version 2.3.0. Details ▾Hide ▴
Evidence considered
  • VCEP declares PP5 not applicable for this VCEP.
Sources
cspec ↗
BS3 VCEPThe RASopathy VCEP declares BS3 not applicable, as functional studies showing no damaging effect are not part of the approved framework. Details ▾Hide ▴
Evidence considered
  • VCEP declares BS3 not applicable.
Sources
cspec ↗
BP1 N/ABP1 in the RASopathy VCEP applies specifically to truncating variants (nonsense, frameshift, canonical splice sites) in genes where gain-of-function is the disease mechanism. NM_002834.4:c.200G>A is a missense variant (p.Gly67Glu), not a truncating variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • BP1 applies only to truncating variants per VCEP specifications.
Sources
cspec ↗
BP3 VCEPSkipped per user directive — BP3 is trivially not applicable (in-frame deletions/insertions in repetitive regions; variant is a missense substitution). Details ▾Hide ▴
Evidence considered
  • Variant is a substitution
  • not an in-frame indel.
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee per the RASopathy VCEP Version 2.3.0. Details ▾Hide ▴
Evidence considered
  • VCEP declares BP6 not applicable for this VCEP.
Sources
cspec ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_002834.4:c.200G>A is a missense variant (p.Gly67Glu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 not applicable.
PS5 N/ASkipped per user directive — not in the assess list for this adjudication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
PTPN11
Transcript
NM_002834.4
Coding (HGVS c.)
NM_002834.4:c.200G>A
Protein (HGVS p.)
NP_002825.3:p.(Gly67Glu)
GRCh38
chr12:112450380 G>A
GRCh37
chr12:112888184 G>A
COSMIC
COSV109433876

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…
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 -151 bp
0.000
SpliceAI acceptor gainat -59 bp
0.020
SpliceAI donor lossat -22 bp
0.000
SpliceAI donor gainat -268 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.890
BayesDel
0.517

How the predictions were used

PP3 SupportingREVEL score is 0.89, which exceeds the RASopathy VCEP threshold of ≥0.7 for PP3 at Supporting strength. Additionally, SpliceAI predicts no significant splice impact (max delta score 0.02), so splicing is not a confounding factor. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.89 (≥0.7 threshold met).
  • SpliceAI max delta 0.02 — no predicted splice alteration.
Sources
revelspliceai ↗
BP4 BP4 requires REVEL score ≤0.3 for missense variants per RASopathy VCEP specifications. The REVEL score for this variant is 0.89, which does not meet the BP4 threshold. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.89 (>0.3 threshold for BP4).
Sources
revel
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_002834.4:c.200G>A is a missense variant (p.Gly67Glu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous
  • BP7 not applicable.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.516839.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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 0.020 Open source ↗
ClinVar Captured ClinVar source record 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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.89. BayesDel score = 0.516839.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109433876, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.