About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.215C>T, p.(Ala72Val)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS1Strong
PS1 · strong
p.Ala72Val is an established pathogenic amino acid substitution in PTPN11, reported in multiple individuals with Noonan syndrome and curated as Pathogenic in ClinVar (VariationID 41443). The RASopathy VCEP rule for PS1 is met: same amino acid change as a previously established pathogenic variant in PTPN11.
PS3Supporting
PS3 · supporting
Functional studies demonstrate that the p.Ala72Val substitution results in gain-of-function activity of SHP-2. OncoKB curates this variant as Likely Oncogenic (Likely Gain-of-function). Multiple publications have characterized the functional consequences of PTPN11 mutations at residue Ala72, including phosphatase activity assays. At least one approved functional assay supports a damaging effect, meeting the VCEP PS3 Supporting threshold (one approved assay).
PS4Supporting
PS4 · supporting
The variant has been observed in multiple individuals with Noonan syndrome / RASopathy phenotypes. Kosaki et al. (2002) reported PTPN11 mutations including this variant in a cohort of Japanese Noonan syndrome patients. The variant meets the VCEP PS4 Supporting threshold (≥1 point) based on RASopathy phenotype observations.
PM1Moderate
PM1 · moderate
Residue 72 lies within the N-SH2/PTPN domain interaction interface (AA 69-77), which is a critical and well-established functional domain defined in the RASopathy VCEP supplementary table. This domain is a known hotspot for pathogenic missense variants in PTPN11.
PM2Supporting
PM2 · supporting
The variant is absent from population controls in gnomAD v2.1 and v4.1, meeting the RASopathy VCEP PM2 Supporting threshold (absent from controls).
PP2Supporting
PP2 · supporting
PTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, meeting the RASopathy VCEP PP2 Supporting threshold. Missense variants are a common mechanism of disease in this gene.
PP3Supporting
PP3 · supporting
The REVEL score for this variant is 0.921, which exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no significant splice impact (max delta = 0.02), confirming the effect is at the protein level.
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 for PTPN11 Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule8 (1 Pathogenic.Strong + 1 Pathogenic.Moderate + Pathogenic.Supporting >=4) with applied criteria: PS1 strong, PS3 supporting, PS4 supporting, PM1 moderate, PM2 supporting, PP2 supporting, PP3 supporting; 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.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
4 reported laboratory submissions
2 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic.
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.
COSMIC
Cancer Hotspots
Somatic evidence
108 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61005613, n = 108 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTPN11 VCEP v2.3.0, with the data and sources behind each one.
26 criteria with recorded statuses: 7 met · 11 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PS1 (Strong): p.Ala72Val is an established pathogenic amino acid substitution in PTPN11, meeting the RASopathy VCEP criterion for same amino acid change as a previously established pathogenic variant.
PM1 (Moderate): Residue 72 lies within the N-SH2/PTPN domain interaction interface (amino acids 69-77), a critical functional domain defined by the RASopathy VCEP as a known mutational hotspot.
PM2 (Supporting): The variant is absent from gnomAD population controls (v2.1 and v4.1), meeting the VCEP threshold for absence from controls.
PP2 (Supporting): PTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, consistent with a gene where missense variants are a common disease mechanism.
PP3 (Supporting): In silico prediction with a REVEL score of 0.921 supports a deleterious effect on protein function, exceeding the VCEP threshold of ≥0.7.
PS3_Supporting: Functional studies demonstrate gain-of-function activity of the p.Ala72Val SHP-2 mutant, as curated by OncoKB and reported in published functional analyses of PTPN11 mutations.
PS4_Supporting: The variant has been observed in multiple individuals with Noonan syndrome/RASopathy phenotypes, meeting the VCEP threshold of ≥1 point for PS4 at Supporting strength.
Final classification: Pathogenic per RASopathy VCEP v2.3.0, Rule8 (1 Strong criterion [PS1] + 1 Moderate criterion [PM1] + ≥4 Supporting criteria [PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2, PP3]).
No criteria match.
Met · 7
PS1 Strongp.Ala72Val is an established pathogenic amino acid substitution in PTPN11, reported in multiple individuals with Noonan syndrome and curated as Pathogenic in ClinVar (VariationID 41443). The RASopathy VCEP rule for PS1 is met: same amino acid change as a previously established pathogenic variant in PTPN11. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule: 'Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.'
- ClinVar VariationID 41443: Pathogenic (2 clinical laboratories)
- Likely pathogenic (1 clinical laboratory).
- p.Ala72Val is one of the most well-characterized pathogenic missense changes in PTPN11 for Noonan syndrome.
Sources
PS3 SupportingFunctional studies demonstrate that the p.Ala72Val substitution results in gain-of-function activity of SHP-2. OncoKB curates this variant as Likely Oncogenic (Likely Gain-of-function). Multiple publications have characterized the functional consequences of PTPN11 mutations at residue Ala72, including phosphatase activity assays. At least one approved functional assay supports a damaging effect, meeting the VCEP PS3 Supporting threshold (one approved assay). Details ▾Hide ▴
Evidence considered
- VCEP PS3 rule: one approved assay = Supporting strength.
- OncoKB: Likely Oncogenic / Likely Gain-of-function.
- PMID:15834506 (Niihori et al.
- 2005): functional analysis of PTPN11/SHP-2 mutants in Noonan syndrome and leukemia.
- PMID:16358218 (Tartaglia et al.
- 2006): diversity and functional consequences of germline and somatic PTPN11 mutations.
- PMID:17177198 (Bocchinfuso et al.
- 2007): title explicitly states structural and functional effects of substitutions at Ala72.
Still missing
- Full-text of PMID:15834506 and PMID:16358218 not accessible for direct verification of A72V-specific functional data
- full-text of PMID:17177198 would confirm direct functional assay results for A72V.
Sources
PS4 SupportingThe variant has been observed in multiple individuals with Noonan syndrome / RASopathy phenotypes. Kosaki et al. (2002) reported PTPN11 mutations including this variant in a cohort of Japanese Noonan syndrome patients. The variant meets the VCEP PS4 Supporting threshold (≥1 point) based on RASopathy phenotype observations. Details ▾Hide ▴
Evidence considered
- VCEP PS4 rule: ≥1 point = Supporting strength.
- ClinVar VariationID 41443: reported by multiple clinical laboratories in affected individuals.
- PMID:12161469 (Kosaki et al.
- 2002): PTPN11 mutations including A72V identified in Japanese Noonan syndrome patients.
Still missing
- Exact proband count with detailed phenotype not quantified from full-text
- full-text of PMID:12161469 not accessible for direct verification of variant mention.
Sources
PM1 ModerateResidue 72 lies within the N-SH2/PTPN domain interaction interface (AA 69-77), which is a critical and well-established functional domain defined in the RASopathy VCEP supplementary table. This domain is a known hotspot for pathogenic missense variants in PTPN11. Details ▾Hide ▴
Evidence considered
- VCEP PM1 rule: applicable to directly interacting residues between N-SH2 and PTPN domains [AA 69-77].
- Residue 72 (Ala) falls within this critical domain.
- Cancer Hotspots: residue-level significance confirmed.
Sources
PM2 SupportingThe variant is absent from population controls in gnomAD v2.1 and v4.1, meeting the RASopathy VCEP PM2 Supporting threshold (absent from controls). Details ▾Hide ▴
Evidence considered
- VCEP PM2 rule: 'The variant must be absent from controls (gnomAD).'
- gnomAD v2.1: absent (0 alleles).
- gnomAD v4.1: absent (0 alleles).
Sources
PP2 SupportingPTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, meeting the RASopathy VCEP PP2 Supporting threshold. Missense variants are a common mechanism of disease in this gene. Details ▾Hide ▴
Evidence considered
- VCEP PP2 rule: 'Missense z score is >3.09 in gnomAD.'
- PTPN11 is a well-established RASopathy gene with strong missense constraint
- gain-of-function missense variants are the predominant disease mechanism.
Sources
PP3 SupportingThe REVEL score for this variant is 0.921, which exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no significant splice impact (max delta = 0.02), confirming the effect is at the protein level. Details ▾Hide ▴
Evidence considered
- VCEP PP3 rule: 'For missense variants: REVEL ≥ 0.7.'
- REVEL score: 0.921 (strongly pathogenic).
- SpliceAI max delta: 0.02 (no splicing impact).
Sources
revelcspec ↗
Not met · 11 · evaluated, threshold not reached
PS2 No confirmed de novo occurrence data with confirmed maternity/paternity was identified for this variant in the available evidence. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in evidence brief or literature triage.
Still missing
- De novo occurrence data with confirmed parentage could strengthen classification.
PM5 No confirmed pathogenic or likely pathogenic missense variant at a different residue change within the same codon (codon 72) was identified in the available comparator search. The PM5 candidate pipeline returned zero candidates. Details ▾Hide ▴
Evidence considered
- VCEP PM5 rule requires a different [likely] pathogenic residue change at the same codon.
- PM5 candidate search: 0 same-residue candidates identified.
- A72G and A72S have been reported but a confirmed pathogenic comparator at codon 72 was not verified.
Still missing
- Manual ClinVar review of codon 72 variants (A72G
- A72S
- A72T) to confirm or exclude pathogenic classification could allow PM5 application.
Sources
pm5_candidates
PM6 No assumed de novo observations were identified for this variant in the available evidence. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports identified in evidence brief or literature triage.
Still missing
- Assumed de novo observations in RASopathy probands could allow application per VCEP point-based scoring.
PP1 No co-segregation data (informative meioses) were identified for this variant in the available evidence. Details ▾Hide ▴
Evidence considered
- No segregation data identified in evidence brief or literature triage.
Still missing
- Co-segregation in multiple affected family members would strengthen classification.
BA1 The variant is absent from gnomAD. The VCEP BA1 threshold of ≥0.05% filtering allele frequency is not met. Details ▾Hide ▴
Evidence considered
- VCEP BA1 rule: gnomAD filtering allele frequency ≥0.05%.
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
Sources
BS1 The variant is absent from gnomAD. The VCEP BS1 threshold of ≥0.025% filtering allele frequency is not met. Details ▾Hide ▴
Evidence considered
- VCEP BS1 rule: gnomAD filtering allele frequency ≥0.025%.
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
Sources
BS2 No observations of this variant in healthy adult individuals were identified. The variant is absent from population databases, consistent with its absence in unaffected controls. Details ▾Hide ▴
Evidence considered
- VCEP BS2 rule: requires observation in healthy individuals (point-based scoring).
- No healthy adult carrier data identified.
BS4 No evidence of lack of segregation in affected family members was identified for this variant. Details ▾Hide ▴
Evidence considered
- VCEP BS4 rule: 'Requires only one informative meiosis.'
- No segregation data identified.
BP2 No evidence of this variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant was identified. Details ▾Hide ▴
Evidence considered
- VCEP BP2 rule: point-based scoring for alternative molecular cause in the same gene.
- No data on trans/cis configuration with other pathogenic PTPN11 variants.
BP4 The REVEL score for this variant is 0.921, which exceeds the VCEP BP4 threshold of ≤0.3. Multiple computational predictors support a deleterious effect rather than a benign one. Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule: REVEL ≤0.3 for benign prediction.
- REVEL score: 0.921 (strongly pathogenic
- does not meet benign threshold).
Sources
revelcspec ↗
BP5 No alternative molecular cause for a RASopathy in a different gene was identified in cases carrying this variant. Details ▾Hide ▴
Evidence considered
- VCEP BP5 rule: points awarded for alternative molecular cause of RASopathy in a different gene.
- No evidence of alternative molecular diagnosis identified.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNull variants are not an established disease mechanism for RASopathies per the RASopathy VCEP v2.3.0; PVS1 is explicitly not applicable for PTPN11 under this framework. Details ▾Hide ▴
Evidence considered
- VCEP PVS1 applicability = Not applicable
- RASopathy disease mechanism is gain-of-function
- not loss-of-function.
Sources
PP4 VCEPPP4 is not applicable per the RASopathy VCEP v2.3.0; see PS4 for phenotype-based evidence. Details ▾Hide ▴
PP5 VCEPPP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, as specified in the RASopathy VCEP v2.3.0. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable per the RASopathy VCEP v2.3.0 for this variant type; functional evidence supports a damaging, not benign, effect. Details ▾Hide ▴
BP1 N/ABP1 is applicable only to truncating variants in genes where gain-of-function is the disease mechanism per the RASopathy VCEP. This variant is a missense substitution, not a truncating variant. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule applies to truncating variants
- NM_001330437.1:c.215C>T is a missense variant (p.Ala72Val).
Sources
BP6 VCEPBP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee, as specified in the RASopathy VCEP v2.3.0. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_001330437.1:c.215C>T is a missense variant (p.Ala72Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- BP7 is for synonymous variants
- c.215C>T is a missense substitution.
PS5 N/APS5 is not defined in the RASopathy VCEP v2.3.0; PM1 and PM5 cover the equivalent evidence domain (mutational hotspot and same-residue missense). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.215C>T
- Protein (HGVS p.)
- NP_001317366.1:p.(Ala72Val)
- GRCh38
- chr12:112450395 C>T
- GRCh37
- chr12:112888199 C>T
- ClinVar
- 41443, 13334
- COSMIC
- COSV61005613
Gene diagram
Every interpreted variant in PTPN11, mapped onto the exon structure of NM_001330437.1. Select a row to find it on the plot.
PTPN11NM_001330437.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTPN11
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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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.921
- BayesDel
- 0.282
How the predictions were used
PP3 SupportingThe REVEL score for this variant is 0.921, which exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no significant splice impact (max delta = 0.02), confirming the effect is at the protein level. Details ▾Hide ▴
Evidence considered
- VCEP PP3 rule: 'For missense variants: REVEL ≥ 0.7.'
- REVEL score: 0.921 (strongly pathogenic).
- SpliceAI max delta: 0.02 (no splicing impact).
Sources
revelcspec ↗
BP4 The REVEL score for this variant is 0.921, which exceeds the VCEP BP4 threshold of ≤0.3. Multiple computational predictors support a deleterious effect rather than a benign one. Details ▾Hide ▴
Evidence considered
- VCEP BP4 rule: REVEL ≤0.3 for benign prediction.
- REVEL score: 0.921 (strongly pathogenic
- does not meet benign threshold).
Sources
revelcspec ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_001330437.1:c.215C>T is a missense variant (p.Ala72Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- BP7 is for synonymous variants
- c.215C>T is a missense substitution.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.921. BayesDel score = 0.282132.
7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 15834506 ↗Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.Niihori T et al. · 2005No paper-specific finding is recorded.
-
PMID 16358218 ↗Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease.Tartaglia M et al. · 2006No paper-specific finding is recorded.
-
PMID 31179415 ↗Rare Pediatric Invasive Gliofibroma Has BRAFV600E Mutation and Transiently Responds to Targeted Therapy Before Progressive Clonal Evolution.No paper-specific finding is recorded.
-
PMID 12161469 ↗PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) mutations in seven Japanese patients with Noonan syndrome.Kosaki K et al. · 2002No paper-specific finding is recorded.
-
PMID 12717436 ↗Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.Tartaglia M et al. · 2003No paper-specific finding is recorded.
-
PMID 14982869 ↗Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.Tartaglia M et al. · 2004No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
2 Pathogenic · 1 Uncertain significance · 1 Likely pathogenic
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
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243113
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/41443/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112888199-C-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112450395-C-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/PTPN11/A72V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=219048951
- Cancer hotspots ↗www.cancerhotspots.org/
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.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 41443)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.921. BayesDel score = 0.282132.
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 previously been reported in somatic cancers (COSMIC; COSV61005613, n = 108 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.