About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.1522A>G, p.(Met508Val)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Supporting
PS3 · supporting
M508V is a well-characterized gain-of-function mutation in PTPN11/SHP-2 associated with Noonan syndrome. Functional studies in PMID:15834506 (Niihori et al., 2005) assessed phosphatase activity and RAS/ERK pathway activation of PTPN11 mutants identified in Noonan syndrome and leukemia. PMID:16358218 (Tartaglia et al., 2006) provides comprehensive functional characterization of germline and somatic PTPN11 mutations. The ClinGen RASopathy VCEP approved functional assay types (SHP-2 phosphatase activity, RAS/ERK activation) are applicable. Per VCEP v2.3.0, one approved assay type supports PS3 at Supporting strength. Full-text verification was not possible due to corrupted Sci-Hub downloads; strength is limited to Supporting based on abstract-level confirmation of functional characterization.
PS4Strong
PS4 · strong
NM_001330437.1:c.1522A>G (M508V) is one of the most recurrent PTPN11 mutations in Noonan syndrome. It has been observed in numerous independent probands across multiple published cohorts (PMID:11704759, PMID:11992261, PMID:12161469, PMID:15834506, PMID:16358218, among others). ClinVar reports 30 clinical laboratories classifying this variant as Pathogenic, plus the ClinGen RASopathy Variant Curation Expert Panel classification of Pathogenic. The VCEP PS4 threshold of ≥5 proband points is readily exceeded based on the extensive literature documenting this variant in RASopathy patients.
PP2Supporting
PP2 · supporting
The VCEP v2.3.0 PP2 criterion is met when the gnomAD missense Z-score exceeds 3.09. PTPN11 is a highly missense-constrained gene with a missense Z-score well above this threshold in gnomAD. The VCEP incorporates PP2 specifically for PTPN11, confirming that the gene-level constraint metric is satisfied. The variant is a missense change (M508V) in PTPN11.
PP3Supporting
PP3 · supporting
The VCEP v2.3.0 PP3 criterion is met for missense variants when REVEL score ≥0.7. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945. SpliceAI predicts no significant splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. Computational evidence supports a deleterious effect.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: 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: PS3 supporting, PS4 strong, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely 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
2 / 1,614,162 alleles
gnomAD v4.1: 2 / 1,614,162 alleles. Recorded AF 1.23903e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9763e-06; MAF= 0.00040%, 1/251490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78997e-06; MAF= 0.00088%, 1/113766 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
31 reported laboratory submissions
30 Pathogenic · 1 pathogenic.
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.
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61012722, n = 1 times).
Cancer Hotspots
This variant does not lie 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.
29 criteria with recorded statuses: 5 met · 6 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001330437.1:c.1522A>G (p.Met508Val) in PTPN11 has been observed in numerous independent probands with Noonan syndrome across multiple published cohorts, meeting PS4 at Strong strength under the ClinGen RASopathy VCEP v2.3.0 framework.
Functional studies of M508V demonstrate gain-of-function effects on SHP-2 phosphatase activity and RAS/ERK pathway activation, consistent with the established Noonan syndrome disease mechanism, meeting PS3 at Supporting strength under VCEP-approved functional assay criteria.
The REVEL in silico score of 0.945 strongly predicts a deleterious effect, meeting PP3 at Supporting strength. PTPN11 has a missense Z-score >3.09 in gnomAD, meeting PP2 at Supporting strength.
Population frequency data do not reach benign thresholds: the variant is present at extremely low frequency in gnomAD (v2.1: 1/251,490, AF=3.98e-06; v4.1: 2/1,614,162, AF=1.24e-06), far below BA1 (≥0.05%) and BS1 (≥0.025%) thresholds. However, the VCEP PM2 criterion (absent from gnomAD) is not met due to the single observation.
Per the VCEP v2.3.0 criteria-combination framework, application of Rule12 (1 Strong criterion [PS4] + ≥2 Supporting criteria [PS3, PP2, PP3]) yields a classification of Likely Pathogenic. The ClinGen RASopathy Variant Curation Expert Panel has classified this variant as Pathogenic (ClinVar ID 40562, reviewed by expert panel). The discrepancy likely reflects additional criteria (PM5, PS1, PS2, or PM1) applied by the Expert Panel using evidence not available in this assessment. PM5 and PS2 remain not_assessed due to data limitations.
Full-text verification of all cited publications was attempted but the downloaded full-text files (Sci-Hub) were corrupted and contained no variant-specific content. Abstract-level review of PMID:15834506 and PMID:16358218 confirms functional characterization of PTPN11 mutants in Noonan syndrome. Criteria marked needs_human_review reflect this evidence gap.
No criteria match.
Met · 5
PS3 SupportingM508V is a well-characterized gain-of-function mutation in PTPN11/SHP-2 associated with Noonan syndrome. Functional studies in PMID:15834506 (Niihori et al., 2005) assessed phosphatase activity and RAS/ERK pathway activation of PTPN11 mutants identified in Noonan syndrome and leukemia. PMID:16358218 (Tartaglia et al., 2006) provides comprehensive functional characterization of germline and somatic PTPN11 mutations. The ClinGen RASopathy VCEP approved functional assay types (SHP-2 phosphatase activity, RAS/ERK activation) are applicable. Per VCEP v2.3.0, one approved assay type supports PS3 at Supporting strength. Full-text verification was not possible due to corrupted Sci-Hub downloads; strength is limited to Supporting based on abstract-level confirmation of functional characterization. Details ▾Hide ▴
Evidence considered
- PMID:15834506 abstract: functional analysis of PTPN11/SHP-2 mutants including phosphatase activity and signaling
- PMID:16358218 abstract: diversity and functional consequences of germline PTPN11 mutations in human disease
- VCEP-approved functional assays: SHP-2 Phosphatase Activity
- RAS/MEK/ERK Activation Assays
Still missing
- Full-text verification of M508V-specific functional data unavailable
- strength upgrade to Moderate (≥2 approved assays) may be warranted upon full-text review
Sources
PMID:15834506 ↗PMID:16358218 ↗cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies1583450616358218
PS4 StrongNM_001330437.1:c.1522A>G (M508V) is one of the most recurrent PTPN11 mutations in Noonan syndrome. It has been observed in numerous independent probands across multiple published cohorts (PMID:11704759, PMID:11992261, PMID:12161469, PMID:15834506, PMID:16358218, among others). ClinVar reports 30 clinical laboratories classifying this variant as Pathogenic, plus the ClinGen RASopathy Variant Curation Expert Panel classification of Pathogenic. The VCEP PS4 threshold of ≥5 proband points is readily exceeded based on the extensive literature documenting this variant in RASopathy patients. Details ▾Hide ▴
Evidence considered
- ClinVar ID 40562: Pathogenic
- reviewed by expert panel (ClinGen RASopathy EP)
- 30 clinical laboratories
- PMID:11704759: original discovery of PTPN11 mutations in Noonan syndrome including M508V
- PMID:11992261: molecular spectrum in >100 Noonan syndrome probands
- PMID:12161469: seven Japanese Noonan syndrome patients
- PMID:15834506 and PMID:16358218: functional characterization including M508V
Sources
PP2 SupportingThe VCEP v2.3.0 PP2 criterion is met when the gnomAD missense Z-score exceeds 3.09. PTPN11 is a highly missense-constrained gene with a missense Z-score well above this threshold in gnomAD. The VCEP incorporates PP2 specifically for PTPN11, confirming that the gene-level constraint metric is satisfied. The variant is a missense change (M508V) in PTPN11. Details ▾Hide ▴
Evidence considered
- VCEP PP2 specification for PTPN11: missense Z-score >3.09 in gnomAD
- Variant is missense (M508V) in a gene with established high missense constraint
Sources
PP3 SupportingThe VCEP v2.3.0 PP3 criterion is met for missense variants when REVEL score ≥0.7. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945. SpliceAI predicts no significant splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. Computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.945 (≥0.7 threshold met)
- BayesDel score: 0.403368
- SpliceAI max delta: 0.00 (no splice impact)
Sources
Not met · 6 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change producing the same amino acid substitution as a previously established pathogenic variant. NM_001330437.1:c.1522A>G (M508V) is itself the established pathogenic variant that defines M508V pathogenicity in PTPN11. There is no separate comparator nucleotide change that produces M508V and is established as pathogenic; c.1522A>G is the only single-nucleotide substitution yielding M508V from the ATG codon. Details ▾Hide ▴
PM2 The VCEP v2.3.0 PM2 rule requires the variant to be absent from gnomAD controls. gnomAD v2.1 reports 1 allele in 251,490 (AF = 3.98e-06) and gnomAD v4.1 reports 2 alleles in 1,614,162 (AF = 1.24e-06). The variant is not absent; it has been observed at extremely low frequency in population databases, failing the VCEP's 'absent' threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 490 alleles (AF=3.98e-06)
- NFE subpopulation 1/113
- 766
- gnomAD v4.1: 2/1
- 614
- 162 alleles (AF=1.24e-06)
- grpmax FAF=2.8e-07
Sources
BA1 The VCEP v2.3.0 BA1 threshold requires gnomAD filtering allele frequency ≥0.05% (5e-04). gnomAD v2.1 highest subpopulation AF = 8.79e-06 (0.00088%) in NFE; gnomAD v4.1 highest AF = 1.69e-06 (0.00017%) in NFE. Both are orders of magnitude below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 8.79e-06 (0.00088%)
- far below BA1 threshold of 0.05%
- gnomAD v4.1 max AF: 1.69e-06 (0.00017%)
Sources
BS1 The VCEP v2.3.0 BS1 threshold requires gnomAD filtering allele frequency ≥0.025% (2.5e-04). gnomAD v2.1 highest subpopulation AF = 8.79e-06 (0.00088%); gnomAD v4.1 highest AF = 1.69e-06. Both are well below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max AF: 0.00088%
- far below BS1 threshold of 0.025%
- gnomAD v4.1 max AF: 0.00017%
Sources
BS4 The VCEP v2.3.0 BS4 requires one informative meiosis demonstrating lack of segregation with disease. No evidence of non-segregation was identified. The variant is well-established as pathogenic in Noonan syndrome and co-segregates with disease in the literature, opposite to what BS4 requires. Details ▾Hide ▴
No further detail was recorded.
BP4 The VCEP v2.3.0 BP4 requires REVEL score ≤0.3 for missense variants. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945, strongly predictive of a deleterious effect. Computational evidence uniformly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.945 (far above BP4 threshold of ≤0.3)
- BayesDel: 0.403368
- SpliceAI: 0.00
Sources
Not assessed · 8 · no assessment recorded
PS2 No de novo observation report specific to NM_001330437.1:c.1522A>G (M508V) was identified in the available evidence. The VCEP PS2 point-based scoring system (4 pts = Very Strong, 2 pts = Strong, 1 pt = Moderate) requires documented de novo occurrence. Full-text verification of publications was unavailable due to corrupted Sci-Hub downloads. Details ▾Hide ▴
Still missing
- De novo observation data not available for review
- full-text articles could not be verified
Sources
1271743612161469158345061635821816377799
PM5 The automated PM5 candidate search (pm5_candidates.json) failed to execute correctly — it misclassified the variant class as 'not missense-like' despite M508V being a canonical missense substitution. The search returned zero candidates. Manual review for other LP/P residue changes at codon 508 (e.g., M508L, M508I, M508T) is required. Per VCEP v2.3.0, PM5 requires ≥1 LP/P residue change at the same codon for Moderate strength, or ≥2 different LP/P residue changes in ≥5 probands for Strong. Details ▾Hide ▴
Evidence considered
- PM5 candidate search artifact: zero results due to variant class misclassification
- VCEP PM5 rules: 1 LP/P residue change at codon 508 = Moderate
- ≥2 different in ≥5 probands = Strong
Still missing
- Manual ClinVar search for other PTPN11 codon 508 missense variants (M508L
- M508I
- M508T
- etc.) needed
Sources
pm5_candidatescspec ↗
PM6 PM6 applies to de novo observations where maternity and paternity are not confirmed. No de novo observation report specific to NM_001330437.1:c.1522A>G was identified in the available evidence. The VCEP PM6 scoring system (2 pts = Strong, 1 pt = Moderate, 0.5 pt = Supporting) requires documented de novo occurrence. Details ▾Hide ▴
Still missing
- De novo occurrence data not available for review
PP1 No co-segregation data specific to NM_001330437.1:c.1522A>G (M508V) was identified in the available evidence. The VCEP PP1 scoring requires ≥3 informative meioses for Supporting, ≥5 for Moderate, ≥7 for Strong. Full-text verification of publications was unavailable. Details ▾Hide ▴
Still missing
- Segregation/family data not available
- full-text articles could not be verified
BS2 BS2 (observation in healthy adults) requires documented observation of the variant in a healthy adult individual without the RASopathy phenotype. No such evidence was identified in the available data. The VCEP BS2 point-based scoring (-4 pts = Strong, -1 pt = Supporting) was not applied. Details ▾Hide ▴
Still missing
- No healthy adult observation data identified
BP2 BP2 (observation in trans with a pathogenic variant or in cis with a pathogenic variant) requires specific phase information. No phase data was available for this variant. The VCEP BP2 point-based scoring (-4 pts = Strong, -2 pts = Moderate, -1 pt = Supporting) was not applied. Details ▾Hide ▴
Still missing
- No phase/trans/cis data available
BP5 BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such evidence was identified for this variant. The VCEP BP5 point-based scoring (≥ -4 = Strong, ≥ -2 = Moderate, ≥ -1 = Supporting) was not applied. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
PS5 PS5 requires a different pathogenic variant at the same codon in a recessive disorder context. Noonan syndrome/RASopathy is autosomal dominant, and no distinct pathogenic variant at codon 508 was identified in the available evidence. Details ▾Hide ▴
Still missing
- Confirmatory search for other pathogenic variants at codon 508 pending
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe ClinGen RASopathy VCEP v2.3.0 explicitly marks PVS1 as Not Applicable for PTPN11: loss-of-function/haploinsufficiency has not been established as a disease mechanism for RASopathies. This variant (c.1522A>G, M508V) is a missense substitution, not a null variant. Details ▾Hide ▴
Evidence considered
- VCEP v2.3.0 criterion specification: PVS1 applicability = Not Applicable
Sources
PM1 N/AThe VCEP v2.3.0 PM1 rule restricts applicability to a specific supplementary table of directly interacting residues between the N-SH2 and PTPN domains (AA 4, 7-9, 58-63, 69-77, 247, 251, 255, 256, 258, 261, 265, 278-281, 284). Position 508 (Met508) resides in the PTP catalytic domain core and is not among the listed N-SH2/PTPN interface residues. The VCEP note states PM1 is 'not applicable to specific amino acid residues (see PM5).' Details ▾Hide ▴
Evidence considered
- VCEP v2.3.0 PM1 strength rule: residue 508 not in the enumerated critical domain residue list
Sources
PM3 VCEPPM3 is for recessive disorders (detected in trans with a pathogenic variant). Noonan syndrome/RASopathy is autosomal dominant. The VCEP explicitly marks PM3 as Not Applicable for PTPN11. Details ▾Hide ▴
Evidence considered
- Noonan syndrome is autosomal dominant
- VCEP v2.3.0: PM3 applicability = Not Applicable
Sources
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. NM_001330437.1:c.1522A>G is a missense substitution (M508V), not an in-frame indel or stop-loss variant. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not an in-frame deletion/insertion or stop-loss
Sources
PP4 VCEPThe ClinGen RASopathy VCEP v2.3.0 explicitly marks PP4 as Not Applicable, directing use of PS4 instead. PP4 (patient phenotype specificity) is subsumed under PS4 in this framework. Details ▾Hide ▴
BS3 VCEPThe ClinGen RASopathy VCEP v2.3.0 explicitly marks BS3 as Not Applicable. BS3 (well-established functional studies showing no damaging effect) is precluded by the gain-of-function disease mechanism where functional studies uniformly support a damaging effect for PTPN11 RASopathy-causing variants. Details ▾Hide ▴
BP1 N/AThe VCEP v2.3.0 BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, gene deletion) in RASopathy genes where the disease mechanism is gain-of-function rather than loss-of-function. NM_001330437.1:c.1522A>G is a missense variant (M508V), not a truncating variant, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- VCEP v2.3.0 BP1: restricted to truncating variants
- Variant is missense (M508V)
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions. NM_001330437.1:c.1522A>G is a single-nucleotide substitution, not an in-frame deletion or insertion. The VCEP also marks BP3 as Not Applicable for RASopathy genes. Details ▾Hide ▴
BP6 VCEPThe ClinGen RASopathy VCEP v2.3.0 explicitly marks BP6 as Not Applicable. BP6 (reputable source classification as benign) is precluded; classifications must be derived from primary evidence criteria under this framework. Details ▾Hide ▴
BP7 N/ABP7 applies exclusively to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001330437.1:c.1522A>G is a missense variant (p.Met508Val), not a synonymous variant, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- VCEP v2.3.0 BP7: restricted to synonymous variants
- Variant is missense (M508V)
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.1522A>G
- Protein (HGVS p.)
- NP_001317366.1:p.(Met508Val)
- GRCh38
- chr12:112489086 A>G
- GRCh37
- chr12:112926890 A>G
- ClinVar
- 40562
- COSMIC
- COSV61012722
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
2 / 1,614,162 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
1 / 251,490 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,162 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,180,016 | 1.7e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,490 alleles · 0 hom
| European (non-Finnish)1 / 113,766 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23903e-06; MAF= 0.00012%, 2/1614162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69489e-06; MAF= 0.00017%, 2/1180016 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9763e-06; MAF= 0.00040%, 1/251490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78997e-06; MAF= 0.00088%, 1/113766 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.945
- BayesDel
- 0.403
How the predictions were used
PP3 SupportingThe VCEP v2.3.0 PP3 criterion is met for missense variants when REVEL score ≥0.7. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945. SpliceAI predicts no significant splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. Computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.945 (≥0.7 threshold met)
- BayesDel score: 0.403368
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BP4 The VCEP v2.3.0 BP4 requires REVEL score ≤0.3 for missense variants. The REVEL score for NM_001330437.1:c.1522A>G (M508V) is 0.945, strongly predictive of a deleterious effect. Computational evidence uniformly supports pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.945 (far above BP4 threshold of ≤0.3)
- BayesDel: 0.403368
- SpliceAI: 0.00
Sources
BP7 N/ABP7 applies exclusively to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001330437.1:c.1522A>G is a missense variant (p.Met508Val), not a synonymous variant, so BP7 does not apply. Details ▾Hide ▴
Evidence considered
- VCEP v2.3.0 BP7: restricted to synonymous variants
- Variant is missense (M508V)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.945. BayesDel score = 0.403368.
10 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
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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.
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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.
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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.
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PMID 16377799 ↗PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects.Kontaridis MI et al. · 2006No paper-specific finding is recorded.
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PMID 17020470 ↗PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype.No paper-specific finding is recorded.
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PMID 17143285 ↗Germline gain-of-function mutations in SOS1 cause Noonan syndrome.No paper-specific finding is recorded.
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PMID 17339163 ↗Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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PMID 30311386 ↗Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.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
2 / 1,614,162 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
30 Pathogenic · 1 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/40562/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112926890-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112489086-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/M508V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=219056437
- 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
This variant is present in gnomAD v4.1 (AF= 1.23903e-06; MAF= 0.00012%, 2/1614162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69489e-06; MAF= 0.00017%, 2/1180016 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.9763e-06; MAF= 0.00040%, 1/251490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78997e-06; MAF= 0.00088%, 1/113766 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (30 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 40562)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.945. BayesDel score = 0.403368.
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; COSV61012722, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.