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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.188A>G
p.Tyr63Cys  ·  PTPN11
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:15834506 ↗ cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.955. BayesDel score = 0.482421.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61007856, n = 6 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueY63
Hotspots ↗