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.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.2 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.3 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 0.01.4
MAP2K2
Final classification
VUS
MAP2K2 c.383C>A · p.Pro128Gln
MAP2K2
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PS3 moderate, PP5 supporting, PP3 supporting, PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM1PS3PP5PP3PM2
VUS
MAP2K2 c.383C>A
PM1 + PS3 + PP5 + PP3 + PM2
→
VUS
3
PMID:20358587 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_030662.4 · variants mapped to exon structure
MAP2K2
NM_030662.4
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.928. BayesDel score = 0.495827.
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:20358587
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links