Variant classification summary

NM_030662.4:c.383C>A

MAP2K2 · NP_109587.1:p.(Pro128Gln) · NM_030662.4

GRCh37: chr19:4110574 G>T · GRCh38: chr19:4110576 G>T

Gene: MAP2K2 Transcript: NM_030662.4

Final call

VUS

PM1 moderate PS3 moderate PP5 supporting PP3 supporting PM2 supporting

Variant details

Gene

MAP2K2

Transcript

NM_030662.4

Protein

NP_109587.1:p.(Pro128Gln)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

2

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

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.

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PM1	Met	This missense variant affects MAP2K2 codon 128, which falls within the ClinGen RASopathy Expert Panel MAP2K2 critical functional domain spanning amino acids 128-138; this supports PM1 at Moderate strength.	cspec
BP2	Not assessed	No evidence was identified for this variant occurring with an alternative molecular cause that would contribute negative points under the RASopathy-specific BP2 framework.
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the BA1 threshold of 0.05%.	gnomad_v2 gnomad_v4 cspec
PS3	Met	In a published functional study, HEK293T cell assays showed increased downstream ERK phosphorylation for p.Pro128Gln relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study tables also list p.Pro128Gln among pathogenic validation controls for both MEK activation and ERK activation assays, supporting PS3 using two approved assay types.	PMID:20358587 vcep_svi_rasopathy_vcep_v2_approved_functional_studies cspec
PM5	Not assessed	Available evidence reviewed here does not establish whether a different pathogenic missense change at the same codon, or a validated analogous pathogenic residue change under the MAP2K1/MAP2K2 paralog rule, is present for this variant.	cspec vcep_map2k_alignment
PP1	Not assessed	This variant has been reported in an affected family, but the available evidence does not provide enough detail to count informative meioses under the RASopathy PP1 point thresholds.	PMID:20358587 cspec
BS3	N/A	The ClinGen RASopathy Expert Panel marks BS3 as not applicable for MAP2K2 in this framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.	cspec clinvar
BP7	N/A	BP7 is for synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 does not apply.	spliceai cspec
PS1	Not assessed	Available evidence reviewed here does not establish that the same amino acid change, p.Pro128Gln, has been independently reported as a previously established pathogenic variant from a different nucleotide change or validated analogous residue change.	cspec clinvar vcep_map2k_alignment
BP3	N/A	The ClinGen RASopathy Expert Panel marks BP3 as not applicable for MAP2K2 in this framework.	cspec
PP3	Met	For this missense variant, the REVEL score is 0.928, which is above the RASopathy PP3 threshold of 0.7. BayesDel is also positive at 0.495827, supporting a deleterious effect, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.01.	revel bayesdel spliceai cspec
PP4	N/A	The ClinGen RASopathy Expert Panel marks PP4 as not applicable for MAP2K2 in this framework.	cspec
PVS1	N/A	This variant is a missense substitution and does not fall into the null-variant categories used for PVS1 assessment. The MAP2K2 RASopathy specification also marks PVS1 as not applicable.	cspec pvs1_variant_assessment
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the BS1 threshold of 0.025%.	gnomad_v2 gnomad_v4 cspec
BP5	Not assessed	No evidence was identified for an alternative molecular explanation that would contribute negative points under the RASopathy-specific BP5 framework.
BP1	N/A	BP1 in this specification is intended for truncating variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply.	cspec
BP4	Not met	For this missense variant, the REVEL score is 0.928, which is above the BP4 benign threshold of 0.3, so computational evidence does not support a benign effect. BayesDel is also positive at 0.495827 rather than benign, and SpliceAI shows no meaningful splice effect with a maximum delta score of 0.01.	revel bayesdel spliceai cspec
PM3	N/A	The ClinGen RASopathy Expert Panel marks PM3 as not applicable for MAP2K2 in this framework.	cspec
PM4	N/A	PM4 addresses protein length changes such as in-frame insertions or deletions and stop-loss variants. This variant is a missense substitution, so PM4 does not apply.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RASopathy PM2 criterion at Supporting strength for absence from population controls.	gnomad_v2 gnomad_v4 cspec
PS2	Not met	Available case evidence does not support a confirmed de novo occurrence for this variant. Instead, the reported family data describe vertical transmission, so PS2 is not met from the evidence reviewed here.	PMID:20358587 cspec
PS4	Not assessed	This variant has been reported in affected individuals, but the available evidence does not provide enough point-based case data to determine whether the RASopathy PS4 threshold is met.	PMID:20358587 PMID:20301365 clinvar cspec
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals in a manner that would contribute benign points under the RASopathy BS2 framework.	cspec
PP2	N/A	The ClinGen RASopathy Expert Panel marks PP2 as not applicable for MAP2K2 in this framework.	cspec
PM6	Not met	Available case evidence does not support a presumed de novo occurrence for this variant. The reported data instead describe familial transmission, so PM6 is not met from the evidence reviewed here.	PMID:20358587 cspec
BS4	Not assessed	No non-segregation data were identified for this variant. Available evidence does not show the variant tracking away from disease in informative meioses.	PMID:20358587 cspec
BP6	N/A	The ClinGen RASopathy Expert Panel marks BP6 as not applicable for MAP2K2 in this framework.	cspec

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