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LYFE SCIENCES
Project: HERA
NM_001330437.1:c.127C>T
p.Leu43Phe  ·  PTPN11
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Classification rationale
1

The PTPN11 c.127C>T (p.(Leu43Phe), p.(L43F)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with four submissions classified as uncertain significance and one submission classified as likely pathogenic.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which supports PM2 at supporting strength under the PTPN11 RASopathy specification.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Available approved functional-study materials did not provide a variant-specific functional result for p.(Leu43Phe), so PS3 could not be applied from the retrieved evidence.

oncokb ↗
4

Computational evidence supports a damaging missense effect, with REVEL 0.924 above the PP3 threshold of 0.7, BayesDel 0.57613 in a damaging range, and SpliceAI showing no predicted splice effect with a maximum delta score of 0.00.

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
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory).
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 = 0.924. BayesDel score = 0.57613.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL43
Hotspots ↗