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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.1542G>C
p.Gln514His  ·  PTPN11
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Classification rationale
1

The PTPN11 c.1542G>C (p.Gln514His) variant has been observed in somatic cancers in COSMIC (8 occurrences) and has been reported in ClinVar as pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population controls.

gnomad_v2 ↗ gnomad_v4 ↗
3

ClinVar also documents a different nucleotide change producing the same amino acid substitution, supporting PS1, and in silico results support a deleterious missense effect with REVEL 0.94 above the RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.563665, and no predicted splice impact by SpliceAI (max delta score 0.00).

clinvar ↗ cspec ↗ spliceai ↗
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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.94. BayesDel score = 0.563665.
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; COSV61005626, n = 8 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ514
Hotspots ↗