About PTPN11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTPN11 c.188A>G, p.(Tyr63Cys)
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.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting
In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, consistent with a gain-of-function effect. The RASopathy VCEP lists SHP-2 phosphatase activity as an approved PTPN11 assay, supporting PS3 at the supporting level.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious effect. REVEL is 0.955, which is above the PTPN11 VCEP PP3 threshold of 0.7; BayesDel is 0.482421; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting a missense rather than splice-driven interpretation.
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: 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: PS3 supporting, PP3 supporting, PP5 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
14 / 1,613,144 alleles
gnomAD v4.1: 14 / 1,613,144 alleles. Recorded AF 8.6787e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19517e-05; MAF= 0.00120%, 3/251010 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43656e-05; MAF= 0.00544%, 1/18394 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
52 reported laboratory submissions
50 Pathogenic · 1 pathogenic · 1 Uncertain significance.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61007856, n = 6 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.
28 criteria with recorded statuses: 3 met · 6 not met · 9 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
The PTPN11 c.188A>G (p.Tyr63Cys) variant has been reported in ClinVar as pathogenic, including an expert panel assertion from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is present at very low frequency in gnomAD, with AF 0.00120% in v2.1 and AF 0.00087% in v4.1, which is below the RASopathy BA1 and BS1 thresholds but does not meet the PTPN11 VCEP requirement for PM2 because the variant is not absent from controls.
In a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, and the RASopathy VCEP lists this assay type as an approved functional assay for PTPN11, supporting a gain-of-function effect.
Computational evidence supports a deleterious missense effect, with REVEL 0.955 above the PTPN11 VCEP PP3 threshold of 0.7, BayesDel 0.482421, and SpliceAI showing no significant splice impact with a maximum delta score of 0.03.
No criteria match.
Met · 3
PS3 SupportingIn a published functional study, SHP-2 phosphatase assays showed increased activity for Noonan syndrome-associated PTPN11 mutants including p.Tyr63Cys, consistent with a gain-of-function effect. The RASopathy VCEP lists SHP-2 phosphatase activity as an approved PTPN11 assay, supporting PS3 at the supporting level. Details ▾Hide ▴
Rule
PS3 Supporting: one approved assay. PS3 Moderate: two or more different approved assays.
Evidence considered
- Immune complex phosphatase assay with increased activity
- VCEP-approved SHP-2 phosphatase assay for PTPN11
Still missing
- Additional independently approved abnormal assay results for this exact variant were not confirmed here for PS3_Moderate.
Sources
PP3 SupportingComputational evidence supports a deleterious effect. REVEL is 0.955, which is above the PTPN11 VCEP PP3 threshold of 0.7; BayesDel is 0.482421; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting a missense rather than splice-driven interpretation. Details ▾Hide ▴
Rule
For missense variants, PP3 applies when REVEL is at least 0.7.
Evidence considered
- REVEL 0.955
- BayesDel 0.482421
- SpliceAI max delta 0.03
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No previously established pathogenic variant producing the same p.Tyr63Cys amino acid change by a different nucleotide substitution was identified, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant in PTPN11 regardless of nucleotide change.
Evidence considered
- ClinVar exact variant review
- PS1 requires same amino acid change regardless of nucleotide change
Still missing
- A confirmed alternate nucleotide change yielding the same amino acid substitution was not identified.
Sources
PM2 This variant is present in gnomAD, with AF 0.00120% in v2.1 (3/251010 alleles) and AF 0.00087% in v4.1 (14/1613144 alleles). Because the PTPN11 RASopathy specification requires absence from controls for PM2, PM2 is not met. Details ▾Hide ▴
Rule
PM2 Supporting requires absence from controls in gnomAD.
Evidence considered
- gnomAD v2.1 observed
- gnomAD v4.1 observed
Sources
PM5 No qualifying different pathogenic or likely pathogenic missense change at the same codon was identified for application of PM5. The current variant itself cannot be used as its own same-codon comparator. Details ▾Hide ▴
Rule
PM5 Moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5 Strong requires two different pathogenic or likely pathogenic residue changes at the same codon observed in at least five probands.
Evidence considered
- Same-residue PM5 review did not identify a usable comparator
- PM5 requires a different residue change at the same codon
Still missing
- No qualifying alternate pathogenic same-codon comparator was identified from the available review materials.
Sources
BA1 Population frequency is below the BA1 threshold. The highest observed subpopulation frequency is 0.00544% in gnomAD v2.1 East Asian and 0.00223% in gnomAD v4.1 East Asian, both below the RASopathy BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
BA1 applies when the gnomAD filtering allele frequency is at least 0.05%.
Evidence considered
- Highest subpopulation AF 0.00544% in gnomAD v2.1
- Highest subpopulation AF 0.00223% in gnomAD v4.1
Sources
BS1 Population frequency is below the BS1 threshold. The highest observed subpopulation frequency is 0.00544% in gnomAD v2.1 East Asian and 0.00223% in gnomAD v4.1 East Asian, both below the RASopathy BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
BS1 applies when the gnomAD filtering allele frequency is at least 0.025%.
Evidence considered
- Highest subpopulation AF below BS1 threshold in both gnomAD releases
Sources
BP4 Computational evidence does not support BP4. REVEL is 0.955, which is well above the benign BP4 threshold of 0.3, and BayesDel is positive rather than reassuring. SpliceAI predicts no significant splice impact, but this does not overcome the deleterious missense prediction profile. Details ▾Hide ▴
Rule
For missense variants, BP4 applies when REVEL is at most 0.3.
Evidence considered
- REVEL 0.955 exceeds BP4 benign threshold
- BayesDel 0.482421
- SpliceAI max delta 0.03
Sources
Not assessed · 9 · no assessment recorded
PS2 Published reports document de novo PTPN11 variants in Noonan syndrome cohorts, but the available evidence reviewed here does not confirm p.Tyr63Cys as de novo with the parentage information required to assign PS2. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: Moderate at 1 point, Strong at 2 points, Very Strong at 4 points.
Evidence considered
- PMID 12325025 reports Y63C in two unrelated families but does not state de novo for Y63C
- PS2 uses a point-based de novo framework
Still missing
- No exact-variant report with confirmed de novo status and sufficient parentage detail was identified.
Sources
PS4 This variant has been reported in affected individuals with Noonan syndrome, including one report identifying Tyr63Cys among seven mutation-positive Japanese cases and another reporting Tyr63Cys in two unrelated families. However, the available evidence did not provide the point-based proband scoring details needed to assign a PS4 strength under the RASopathy VCEP framework. Details ▾Hide ▴
Rule
PS4 Supporting at 1 point, Moderate at 3 points, Strong at 5 points.
Evidence considered
- Affected-case reports for Tyr63Cys
- PS4 uses point-based thresholds in the RASopathy VCEP framework
Still missing
- Qualifying proband counts and point assignments for the exact variant were not established from the available evidence.
Sources
PM6 The available evidence did not document p.Tyr63Cys as assumed de novo without full parentage confirmation, so PM6 was not assigned. Details ▾Hide ▴
Rule
RASopathy VCEP de novo point system: Supporting at 0.5 point, Moderate at 1 point, Strong at 2 points.
Evidence considered
- Reviewed de novo-related publications did not establish PM6 for Y63C
Still missing
- No exact-variant report with sufficient assumed de novo evidence was identified.
Sources
PP1 No segregation data with enough informative meioses were identified for p.Tyr63Cys, so PP1 was not assigned. Details ▾Hide ▴
Rule
PP1 Supporting requires at least 3 informative meioses, Moderate at least 5, Strong at least 7.
Evidence considered
- Available reports did not provide informative meiosis counts for Y63C
Still missing
- No pedigree-level cosegregation data for the exact variant were identified.
Sources
PP2 The PTPN11 specification allows PP2 when the gene missense z score is greater than 3.09, but the reviewed evidence did not provide the gene-level z score needed to confirm PP2 here. Details ▾Hide ▴
Rule
PP2 applies when the gnomAD missense z score is greater than 3.09.
Evidence considered
- PTPN11 VCEP PP2 rule
Still missing
- Gene-level missense constraint value was not confirmed in the reviewed evidence.
Sources
BS2 The available evidence does not show this variant in the number and context of unaffected individuals required for BS2 under the RASopathy specification. Details ▾Hide ▴
Rule
BS2 uses a point-based unaffected observation framework in the RASopathy specification.
Evidence considered
- Low-frequency population observation without clinical phenotyping
Still missing
- No qualifying unaffected adult observations were identified.
Sources
BS4 No non-segregation evidence for p.Tyr63Cys was identified, so BS4 was not assigned. Details ▾Hide ▴
Rule
BS4 Strong requires one informative meiosis in the RASopathy specification.
Evidence considered
- Reviewed family-level reports did not establish non-segregation for Y63C
Still missing
- No informative family showing lack of segregation for the exact variant was identified.
Sources
BP2 No phase data or alternate pathogenic molecular explanation was identified to support BP2. Details ▾Hide ▴
Rule
BP2 uses a point-based framework in the RASopathy specification.
Evidence considered
- No phase evidence available in reviewed materials
Still missing
- No qualifying in trans or in cis phase data were identified.
Sources
BP5 No alternate molecular diagnosis or independent cause sufficient to support BP5 was identified. Details ▾Hide ▴
Rule
BP5 uses a point-based framework in the RASopathy specification.
Evidence considered
- No alternate-cause evidence in reviewed materials
Still missing
- No qualifying alternate etiology data were identified.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThis is a missense variant, and the PTPN11 RASopathy specification marks PVS1 as not applicable. The generic PVS1 scaffold also indicates that this variant does not fall into a null-variant category. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: PVS1 not applicable.
Evidence considered
- Missense consequence p.Tyr63Cys
- PTPN11 VCEP PVS1 marked not applicable
Sources
PM1 N/AResidue 63 lies within the N-SH2/PTP interaction interface listed in the PTPN11 specification, but the RASopathy VCEP states that PM1 is not applied to specific amino acid residues and directs residue-based evidence to PM5 instead. Because no qualifying same-codon comparator was established, PM1 was not applied. Details ▾Hide ▴
Rule
PM1 applies to listed critical domain residues but is not applicable to specific amino acid residues; see PM5.
Evidence considered
- PM1 domain list includes residues 58-63
- PM1 exclusion for specific amino acid residues
Sources
cspec ↗pm5_candidates
PM3 VCEPPM3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: PM3 not applicable.
Evidence considered
- PTPN11 VCEP applicability table
Sources
PM4 N/AThis is a missense variant and does not cause an in-frame protein length change or stop-loss event, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to in-frame indels in non-repeat regions and stop-loss variants.
Evidence considered
- Missense consequence p.Tyr63Cys
Sources
PP4 VCEPPP4 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: PP4 not applicable.
Evidence considered
- PTPN11 VCEP applicability table
Sources
BS3 VCEPBS3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: BS3 not applicable.
Evidence considered
- PTPN11 VCEP applicability table
Sources
BP1 N/AThis is a missense variant. In the RASopathy specification, BP1 is used for truncating variants in genes without an established loss-of-function disease correlation, so BP1 is not applicable here. Details ▾Hide ▴
Rule
For RASopathies, BP1 is reserved for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
- Missense consequence p.Tyr63Cys
Sources
BP3 VCEPBP3 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: BP3 not applicable.
Evidence considered
- PTPN11 VCEP applicability table
Sources
BP6 VCEPBP6 is not applicable in the PTPN11 RASopathy specification. Details ▾Hide ▴
VCEP rule
PTPN11 RASopathy VCEP: BP6 not applicable.
Evidence considered
- PTPN11 VCEP applicability table
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Missense consequence p.Tyr63Cys
- SpliceAI max delta 0.03
Sources
Identifiers
- Gene
- PTPN11
- Transcript
- NM_001330437.1
- Coding (HGVS c.)
- NM_001330437.1:c.188A>G
- Protein (HGVS p.)
- NP_001317366.1:p.(Tyr63Cys)
- GRCh38
- chr12:112450368 A>G
- GRCh37
- chr12:112888172 A>G
- ClinVar
- 13333
- COSMIC
- COSV61007856
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
14 / 1,613,144 alleles
AF 8.68e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
3 / 251,010 alleles
AF 1.2e-05 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 8.7e-06 · 14 / 1,613,144 alleles · 0 hom · FAF 4.3e-06
| East Asian1 / 44,888 | 2.2e-05 |
| Admixed American1 / 59,982 | 1.7e-05 |
| European (Finnish)1 / 64,040 | 1.6e-05 |
| South Asian1 / 91,062 | 1.1e-05 |
| European (non-Finnish)10 / 1,179,260 | 8.5e-06 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,010 alleles · 0 hom
| East Asian1 / 18,394 | 5.4e-05 |
| Admixed American1 / 34,588 | 2.9e-05 |
| European (non-Finnish)1 / 113,318 | 8.8e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.6787e-06; MAF= 0.00087%, 14/1613144 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22777e-05; MAF= 0.00223%, 1/44888 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19517e-05; MAF= 0.00120%, 3/251010 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43656e-05; MAF= 0.00544%, 1/18394 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.955
- BayesDel
- 0.482
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious effect. REVEL is 0.955, which is above the PTPN11 VCEP PP3 threshold of 0.7; BayesDel is 0.482421; and SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, supporting a missense rather than splice-driven interpretation. Details ▾Hide ▴
Rule
For missense variants, PP3 applies when REVEL is at least 0.7.
Evidence considered
- REVEL 0.955
- BayesDel 0.482421
- SpliceAI max delta 0.03
Sources
BP4 Computational evidence does not support BP4. REVEL is 0.955, which is well above the benign BP4 threshold of 0.3, and BayesDel is positive rather than reassuring. SpliceAI predicts no significant splice impact, but this does not overcome the deleterious missense prediction profile. Details ▾Hide ▴
Rule
For missense variants, BP4 applies when REVEL is at most 0.3.
Evidence considered
- REVEL 0.955 exceeds BP4 benign threshold
- BayesDel 0.482421
- SpliceAI max delta 0.03
Sources
BP7 N/AThis is a missense variant rather than a synonymous, intronic, or non-coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Missense consequence p.Tyr63Cys
- SpliceAI max delta 0.03
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.955. BayesDel score = 0.482421.
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 15834506 ↗Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.No paper-specific finding is recorded.
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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.
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PMID 12325025 ↗PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13.Maheshwari M et al. · 2002No paper-specific finding is recorded.
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PMID 15928039 ↗The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease.No paper-specific finding is recorded.
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PMID 21533187 ↗Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome.No paper-specific finding is recorded.
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PMID 22711529 ↗Counteracting effects operating on Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2) function drive selection of the recurrent Y62D and Y63C substitutions in Noonan syndrome.No paper-specific finding is recorded.
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PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
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PMID 24219368 ↗MAPK activation in mature cataract associated 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
14 / 1,613,144 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
50 Pathogenic · 1 pathogenic · 1 Uncertain significance
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/13333/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-112888172-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-112450368-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001330437.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/PTPN11/Y63C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=187354619
- 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= 8.6787e-06; MAF= 0.00087%, 14/1613144 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22777e-05; MAF= 0.00223%, 1/44888 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19517e-05; MAF= 0.00120%, 3/251010 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43656e-05; MAF= 0.00544%, 1/18394 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (50 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 13333)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.955. BayesDel score = 0.482421.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61007856, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.