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LYFE SCIENCES
Project: HERA
NM_030662.4:c.383C>A
p.Pro128Gln  ·  MAP2K2
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Classification rationale
1

The MAP2K2 c.383C>A (p.Pro128Gln, p.P128Q) variant has not been observed in somatic cancers in COSMIC 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 gnomAD v4.1, supporting rarity in population reference datasets.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In a published functional study, p.Pro128Gln increased downstream ERK phosphorylation relative to wild type, consistent with an activating effect, and RASopathy VCEP-approved functional assay tables include this variant among pathogenic validation controls for MEK and ERK activation assays.

PMID:20358587 ↗
4

Computational evidence supports a damaging effect, with REVEL 0.928 above the MAP2K2 RASopathy PP3 threshold of 0.7 and BayesDel 0.495827 in the damaging direction, while SpliceAI predicts no meaningful splice alteration with a maximum delta score of 0.01.

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
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MAP2K2, an intracellular kinase, is altered by mutation in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.928. BayesDel score = 0.495827.
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.
ResidueP128
Hotspots ↗