Variant classification summary

NM_002755.4:c.167A>C

MAP2K1 · NP_002746.1:p.(Gln56Pro) · NM_002755.4

GRCh37: chr15:66727451 A>C · GRCh38: chr15:66435113 A>C

Gene: MAP2K1 Transcript: NM_002755.4

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

MAP2K1

Transcript

NM_002755.4

Protein

NP_002746.1:p.(Gln56Pro)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: the exact p.Gln56Pro change is previously established as pathogenic, satisfying PS1 strong.

2

Pathogenic evidence: variant-specific studies show increased ERK-pathway activity and transforming effects, satisfying PS3 supporting.

3

Pathogenic evidence: residue 56 lies within the VCEP-approved critical domain at amino acids 43-61, satisfying PM1 moderate.

4

Pathogenic evidence: the variant is absent from gnomAD v2.1 and v4.1, satisfying PM2 supporting.

5

Pathogenic evidence: REVEL 0.841 exceeds the VCEP threshold of 0.7, satisfying PP3 supporting.

Final determination: MAP2K1 VCEP Rule11 is satisfied by one strong pathogenic criterion (PS1) and one moderate pathogenic criterion (PM1), resulting in a Likely Pathogenic classification.

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
PVS1	N/A	Not applicable: the VCEP marks PVS1 as not applicable, and c.167A>C is a missense variant producing p.(Gln56Pro), not a loss-of-function allele.	cspec pvs1_variant_assessment
PS1	Met	Met, strong: the exact p.Q56P amino acid change is previously reported and the matching ClinVar record is Pathogenic from three clinical laboratories.	cspec clinvar PMID:25351745 PMID:22327936 PMID:18632602
PS2	Not assessed	Not assessed: no documented proband-parent testing or confirmed de novo result is available to assign the VCEP's 1-, 2-, or 4-point PS2 thresholds.	cspec
PS3	Met	Met, Supporting: Q56P shows increased ERK-pathway activity in variant-specific studies, but two distinct approved assay types are not established for Moderate strength.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:25351745 PMID:22327936 PMID:18632602
PS4	Not assessed	Not assessed: available reports describe somatic cancer or ECD observations, but provide no VCEP RASopathy point assignment or case-control counts for PS4.	cspec PMID:18632602 PMID:22327936 PMID:25351745 PMID:26566875
PM1	Met	Met, moderate: residue 56 falls within the VCEP-approved critical domain AA 43-61, one of the two explicitly permitted PM1 regions.	cspec vcep_map2k_alignment PMID:25351745
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP requirement that it be absent from gnomAD controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the MAP2K1 RASopathy VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: c.167A>C is a missense substitution causing p.(Gln56Pro), with no in-frame length change or stop-loss consequence for PM4.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: no different likely pathogenic substitution at codon 56 was identified, but the comparator search ended with an HTTP 429 retrieval error.	cspec pm5_candidates PMID:25351745 PMID:22327936 PMID:18632602
PM6	Not assessed	Not assessed: no apparently de novo occurrence with documented parental testing is available to assign the VCEP's 0.5-, 1-, or 2-point PM6 thresholds.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, below the VCEP's minimum threshold of at least 3 for PP1 Supporting.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a gnomAD missense z score >3.09, but no missense z score is available for MAP2K1.	cspec gnomad_v2 gnomad_v4
PP3	Met	Met: REVEL 0.841 exceeds the VCEP PP3 missense threshold of 0.7.	cspec revel
PP4	N/A	Not applicable: the MAP2K1 VCEP explicitly excludes PP4 and directs phenotype-specific evidence to PS4.	cspec
PP5	N/A	Not applicable: the MAP2K1 VCEP explicitly prohibits use of PP5.	cspec
BA1	Not met	Not met: the variant is absent from both gnomAD v2.1 and v4.1, rather than reaching the VCEP's >=0.05% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from both gnomAD v2.1 and v4.1, rather than reaching the VCEP's >=0.025% filtering allele-frequency threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy homozygote or heterozygote observation is available to assign the VCEP's required -4-point or -1-point BS2 score.	cspec
BS3	N/A	Not applicable: the MAP2K1 VCEP marks BS3 as not applicable, and the reviewed studies report activating rather than normal functional results.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative non-segregating meiosis is documented, whereas the VCEP requires one informative meiosis for BS4.	cspec
BP1	N/A	Not applicable: p.Gln56Pro is missense, whereas the VCEP BP1 rule is restricted to specified truncating variant types.	cspec
BP2	Not assessed	Not assessed: no affected-proband evidence documents a second pathogenic MAP2K1 variant, cis/trans phase, and phenotype severity required for ≥ (-1) BP2 point.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 as not applicable, and c.167A>C is a missense variant encoding p.(Gln56Pro).	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.841 is above the VCEP BP4 missense threshold of 0.3.	cspec revel
BP5	Not assessed	Not assessed: no documented alternate causative variant or VCEP BP5 point assignment is available for this case.	cspec
BP6	N/A	Not applicable: the MAP2K1 VCEP explicitly prohibits use of BP6.	cspec
BP7	N/A	Not applicable: c.167A>C is a coding missense variant, not a synonymous, intronic, or non-coding variant covered by BP7.	cspec

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