The MAP2K1 NM_002755.4:c.167A>C (NP_002746.1:p.(Gln56Pro)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61068787, n = 37 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Q56P shows increased ERK-pathway activity in variant-specific studies, but two distinct approved assay types are not established for Moderate strength. Based on available guidelines, this variant is considered to be Likely Pathogenic.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MAP2K1 encodes MEK1, a kinase that relays signals in the MAPK pathway to help regulate cell growth, division, differentiation, development, and survival. Abnormal MAP2K1 signaling is associated with cancer, particularly through activation of the MAPK pathway in cancers such as melanoma, colorectal cancer, and lung cancer, although activating MAP2K1 mutations are uncommon in primary tumors. MAP2K1 alterations can also contribute to resistance to some targeted cancer treatments.
The recorded framework is ClinGen MAP2K1 VCEP v2.3. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, strong: the exact p.Q56P amino acid change is previously reported and the matching ClinVar record is Pathogenic from three clinical laboratories.
Met, Supporting: Q56P shows increased ERK-pathway activity in variant-specific studies, but two distinct approved assay types are not established for Moderate strength.
Met, moderate: residue 56 falls within the VCEP-approved critical domain AA 43-61, one of the two explicitly permitted PM1 regions.
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.
Met: REVEL 0.841 exceeds the VCEP PP3 missense threshold of 0.7.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 strong plus PM1 moderate satisfy MAP2K1 VCEP Rule11, with additional supporting PS3, PM2, and PP3.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.841. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61068787, n = 37 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen MAP2K1 VCEP v2.3, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 3 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No segregation, non-segregation, or de novo family evidence is documented for this variant; therefore PS2, PM6, PP1, and BS4 are not assessed under the MAP2K1 VCEP specifications.
For this phenotype/prevalence group, PP4, PP5, and BP6 are explicitly not applicable under MAP2K1 CSPEC v2.3.
PS4 cannot be assigned because the available reports do not provide the VCEP-required RASopathy point assignment or an evaluable affected-versus-control comparison; BP5 cannot be assigned because no alternate causative variant and point assignment are documented.
Population evidence supports PM2 at Supporting strength because the variant is absent from both queried all-comers gnomAD datasets.
BA1 and BS1 are not met because no gnomAD allele frequency is present, and BS2 is not assessed because the VCEP point-based healthy-individual evidence is unavailable.
No criteria match.
The queried variant produces p.Gln56Pro (p.Q56P). This same amino acid change has been explicitly reported in MAP2K1 by multiple full-text studies, including recurrent Q56P observations and activating functional results, and the exact ClinVar variation is classified Pathogenic by three clinical laboratories. The VCEP permits PS1 at strong strength for the same amino acid change as a previously established pathogenic variant, including analogous MAP2K1 positions.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Applicable for observed analogous residue positions in _MAP2K1_ and _MAP2K2_.
The MAP2K1 VCEP permits PS3 Supporting for one approved assay and PS3 Moderate only for two or more different approved assays. The VCEP approved-functional-studies file was searched for c.167A>C, p.Gln56Pro, and p.Q56P; it contains no variant-specific row or pre-assigned code. Variant-specific functional evidence is present in PMID:25351745, where Q56P increased MEK1-associated kinase activity and ERK phosphorylation and promoted anchorage-independent colony formation, and in PMID:22327936, where MAP2K1(Q56P) markedly increased ERK1/2 phosphorylation and transforming activity. The damaging ERK-pathway readout corresponds to an approved ERK Activation Assay, but the available evidence does not establish two distinct approved assay types for this variant; therefore PS3 is met at Supporting rather than Moderate strength. PMID:18632602 also reports prior transformation competence and approximately 170-fold increased in-vitro ERK phosphorylation activity for MEK1Q56P, but does not provide a second VCEP-approved assay type.
Two or more different approved assays ... One approved assay.
The variant is at residue 56, which lies within the VCEP-defined critical functional domain AA 43-61. The VCEP PM1 rule limits application to the supplementary-table domains AA 43-61 and AA 124-134 and excludes specific-residue evidence as a PM5 route; residue 56 satisfies the domain route. The governing MAP2K-Alignment.xlsx file was searched for c.167A>C, p.Gln56Pro, and p.Q56P, with no matching variant entry; its flattened text contains no residue-56 assignment that overrides the CSPEC domain definition.
Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61, AA 124-134). Not applicable to specific amino acid residues (see PM5).
The governing MAP2K1 VCEP permits PM2 at supporting strength when the variant is absent from controls in gnomAD. The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, so PM2 Supporting is met. The VCEP rule does not specify a non-cancer or exome-only subset, so the available all-comers gnomAD entries are used.
The variant must be absent from controls (gnomAD).
The VCEP PP3 rule covers missense variants through REVEL and assigns PP3 at REVEL >= 0.7; its separate splicing path requires a predicted outcome matching the disease mechanism. This variant is a missense variant, p.(Gln56Pro), and the governing missense predictor is REVEL. The REVEL score is 0.841, which meets the VCEP cutoff. SpliceAI is not used to add a second PP3 observation, so the prediction is not double-counted across computational criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The governing MAP2K1 VCEP requires a gnomAD filtering allele frequency of at least 0.05% for BA1. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying allele frequency is present and BA1 is not met.
GnomAD filtering allele frequency ≥0.05%.
The governing MAP2K1 VCEP requires a gnomAD filtering allele frequency of at least 0.025% for BS1. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no qualifying allele frequency is present and BS1 is not met.
GnomAD filtering allele frequency ≥0.025%.
The VCEP BP4 rule applies to missense variants and requires REVEL <= 0.3. This variant is missense, p.(Gln56Pro), so BP4 is applicable. The available REVEL score is 0.841, which is above the VCEP benign-supporting cutoff and therefore does not satisfy BP4. The SpliceAI no-impact result is not used for BP4 because the VCEP names REVEL for the missense situation, and the same computational prediction is not double-counted across PP3 and BP4.
For missense variants: REVEL ≤0.3.
The VCEP assigns PS2 by de novo evidence points: 4 points for Very Strong, 2 points for Strong, and 1 point for Moderate. The available case evidence contains no documented affected proband, parental testing results, confirmed de novo status, maternity/paternity confirmation, or phenotype-consistency assessment, so no PS2 points can be assigned.
4 Points. ... 2 Points. ... 1 Point.
The VCEP makes PS4 applicable and requires point-based scoring for autosomal-dominant RASopathy cases, with full or reduced points depending on phenotype information. The available literature reports Q56P in somatic lung and gastric cancer cell lines and one ECD patient, not an evaluable RASopathy case-control cohort or a VCEP phenotypic point assignment. Therefore the required PS4 point total cannot be established. No odds ratio or 95% confidence interval can be computed from the available reports because matched affected and unaffected/population control counts are not reported.
Strength adjustment using point-based scoring for autosomal dominant cases with phenotypic specifications: full points awarded with RASopathy phenotypes, reduced points applicable to cases with minimal phenotypic information (i.e. prenatal cases, cases with a clinical order of a RASopathy panel without clinical information, and cases with limited clinical information in other global tests (such as WES)). ... ≥5 points. ... ≥3 points. ... ≥1 points.
The VCEP requires one different likely pathogenic residue change at the same codon for PM5 at moderate strength. The reviewed paper extracts and full-text literature report Q56P but do not establish a different missense substitution at codon 56. The dedicated same-residue comparator collection found no useful candidate and recorded an HTTP 429 retrieval error, so the available evidence cannot establish that the complete comparator search was successful; PM5 is therefore not assessed rather than called not met.
1 [likely] pathogenic residue change at the same codon.
The VCEP assigns PM6 by de novo evidence points: 2 points for Strong, 1 point for Moderate, and 0.5 points for Supporting. The available case evidence does not document an apparently de novo occurrence without the required parental and identity information, so PM6 cannot be scored.
2 Points. ... 1 Point. ... 0.5 Points.
The VCEP assigns PP1 as Supporting for at least 3 informative meioses, Moderate for at least 5 informative meioses, and Strong for at least 7 informative meioses. No informative meioses, affected relatives carrying the variant, or family segregation data are documented, so PP1 cannot be assessed.
≥7 informative meioses. ... ≥5 informative meioses. ... ≥3 informative meioses.
The variant is missense, so the VCEP PP2 rule is applicable in principle, but the required gnomAD missense z score is not present in the available case evidence. No substitute population threshold, predictor, or generic PP2 rule is permitted under the governing instructions.
Missense z score is >3.09 in gnomAD.
The governing MAP2K1 VCEP evaluates BS2 using point-based scoring from phenotypic specifications, with -4 points for strong and -1 point for supporting evidence. The available evidence contains no healthy homozygote or heterozygote observation, no unaffected parent or sibling observation, and no point assignment; therefore BS2 cannot be assessed.
Strength adjustment using point-based scoring based on phenotypic specifications. Phenotypic specifications: based on healthy homozygote or heterozygote individuals, reduced points for apparently unaffected heterozygous individuals, applicable to parent or sibling samples during clinical family evaluations. ... -4 Points. ... -1 Point.
The VCEP requires only one informative meiosis for BS4. The available case evidence documents no informative meiosis or tested unaffected relative who does not carry the variant, so non-segregation cannot be evaluated.
Requires only one informative meiosis.
The VCEP permits BP2 when an alternative molecular cause of a RASopathy is present in the same gene, with phenotype severity consistent with the RASopathy, and assigns supporting strength at ≥ (-1) Point. The available case evidence does not document an affected proband carrying another pathogenic MAP2K1 variant, the phase of any second variant as cis or trans, or the phenotype-severity information needed to award BP2 points. Somatic reports and functional studies for p.Gln56Pro do not establish an allelic relationship in an affected RASopathy proband.
Points are awarded for an alternative molecular cause of a RASopathy in the same gene (and/or in conjunction with BP5) and the phenotype is consistent with expected severity of the RASopathy. ... ≥ (-1) Point.
BP5 is applicable only when an alternative molecular cause of a RASopathy in a different gene, or a phenotype inconsistent with RASopathy fully explained by another causative variant, is documented. The available case evidence does not provide a documented alternate causative variant, its gene, or a VCEP BP5 point assignment. Accordingly, the BP5 point total and strength cannot be evaluated.
Points are awarded for an alternative molecular cause of a RASopathy in a different gene (and/or in conjunction with BP2) and the phenotype is consistent with expected severity of the RASopathy. Points are also awarded for phenotypes inconsistent with a RASopathy and fully explained by a different causative variant (e.g. WES testing). ... ≥ (-4) Points. ... ≥ (-2) Points. ... ≥ (-1) Point.
The governing MAP2K1 VCEP specification marks PVS1 as Not Applicable. This variant is a missense substitution, NM_002755.4:c.167A>C (NP_002746.1:p.(Gln56Pro)) in exon 2, not a loss-of-function consequence; therefore PVS1 is not applied and no strength tier is assigned.
Not Applicable
The MAP2K1 RASopathy VCEP explicitly marks PM3 as not applicable. Therefore, the recessive-disorder trans-phase criterion is not evaluated for this autosomal-dominant RASopathy framework, regardless of the available variant observations.
Not applicable.
The VCEP PM4 rule is limited to protein-length-change application in a gene with no known repetitive areas. The observed variant is a missense substitution, p.(Gln56Pro), with no protein-length change, so the PM4 variant-type requirement is not met and PM4 is not applicable.
No known repetitive areas in gene. Use as described.
The MAP2K1 VCEP explicitly marks PP4 not applicable and directs phenotype-specific assessment to PS4.
Not applicable, see PS4.
The MAP2K1 VCEP explicitly states that PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The MAP2K1 VCEP explicitly marks BS3 as not applicable. The reviewed variant-specific studies report damaging or activating effects rather than a validated normal-function result, but that evidence does not change the VCEP's applicability designation.
Not applicable
The variant is a missense substitution, p.Gln56Pro. The VCEP BP1 rule applies to truncating variants, specifically nonsense, frameshift, canonical splice-site, initiation-codon, entire-gene, or multi-exon deletions in the stated gene context; none describes this missense variant.
This rule has contraindications for use with RASopathies. Given the disease mechanism is gain-of-function for RASopathies, BP1 should be used for any truncating variant (nonsense, frameshift, affects canonical splice sites, initiation codon, entire gene or multi exon deletion) in genes without established LOF correlation to disease. See the supplemental material regarding dosage sensitivity information for each individual gene and potential association to disorders associated with LOF variants.
The governing MAP2K1 VCEP specification marks BP3 as Not Applicable. The variant is a missense substitution rather than an applicable benign in-frame change in a repetitive region, so BP3 is not applied.
Not Applicable
The MAP2K1 VCEP explicitly marks BP6 not applicable and states that the criterion is not for use.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP BP7 rule is limited to synonymous variants and additionally covers intronic positions other than canonical splice sites or non-coding variants. NM_002755.4:c.167A>C is a coding missense variant producing p.(Gln56Pro), so it is outside BP7 scope. BP7 is therefore not_applicable without evaluating a predictor score.
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
Every interpreted variant in MAP2K1, mapped onto the exon structure of NM_002755.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
The VCEP PP3 rule covers missense variants through REVEL and assigns PP3 at REVEL >= 0.7; its separate splicing path requires a predicted outcome matching the disease mechanism. This variant is a missense variant, p.(Gln56Pro), and the governing missense predictor is REVEL. The REVEL score is 0.841, which meets the VCEP cutoff. SpliceAI is not used to add a second PP3 observation, so the prediction is not double-counted across computational criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The VCEP BP4 rule applies to missense variants and requires REVEL <= 0.3. This variant is missense, p.(Gln56Pro), so BP4 is applicable. The available REVEL score is 0.841, which is above the VCEP benign-supporting cutoff and therefore does not satisfy BP4. The SpliceAI no-impact result is not used for BP4 because the VCEP names REVEL for the missense situation, and the same computational prediction is not double-counted across PP3 and BP4.
For missense variants: REVEL ≤0.3.
The VCEP BP7 rule is limited to synonymous variants and additionally covers intronic positions other than canonical splice sites or non-coding variants. NM_002755.4:c.167A>C is a coding missense variant producing p.(Gln56Pro), so it is outside BP7 scope. BP7 is therefore not_applicable without evaluating a predictor score.
A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. This rule is also applicable for intronic positions (except canonical splice sites) or non-coding variants and should be used in conjunction with BP4.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.841. BayesDel score = 0.49396.
7 paper records listed. 3 cited in the classification.
Whereas no lines carried the K57N mutation, we did find that NCI-H1437 cells harbor a mutation encoding a Q56P MEK1 variant (data not shown).
Location Introduction, paragraph 3; Results, final paragraph; Discussion, paragraph 3
Context Screening of 85 NSCLC cell lines; NCI-H1437 characterization; prior rat-fibroblast transformation study and in vitro MEK1Q56P-GST assay measuring phosphorylation of recombinant ERK.
Sequencing of this position in OCUM-1 genomic DNA confirmed the presence of this substitution, which results in replacement of a glutamine at amino acid position 56 with proline.
Location Results, “Identification of MAP2K1(Q56P) in OCUM-1 cells”; “Transforming ability of MAP2K1(Q56P)”
Context OCUM-1 scirrhous-type gastric cancer cell line; retroviral focus-formation assay in mouse 3T3 fibroblasts; tumorigenicity assay in nude mice; MAP2K1 inhibitor AZD6244 treatment; ERK1/2 phosphorylation assay in HEK293 cells.
Specific MEK1 mutations interrogated in the extended panels included Q56P, K57N and D67N. ... Amongst the 26 cases of MEK1 mutated lung cancer identified at the two institutions, K57N was the most common mutation detected, encompassing 77% (20/26) of all variants while all remaining cases harbored the Q56P (6/26). ... Western blot analysis demonstrated increased kinase activity in all mutants, except for the D67N. ... Anchorage independent growth was also assessed for mutated cell lines harboring F53L, Q56P, K57N and D67N mutations. Colony formation after 4 week culture in soft agar showed colonies of greater than 150 microns in the 4 mutant cell lines tested but not in the control or wild-type MEK1 cells. Treatment with 1 μM Selumetinib inhibited colony formation in all the mutated cell lines.
Location Materials and Methods, Tissue procurement and mutational profiling; Results, Spectrum of MEK1 mutations; Results, Functional characterization of MEK1 mutants
Context Lung adenocarcinoma mutation-screening cohort of 5330 patients, including 26 institution-identified MEK1-mutated cases; MAP2K1 mutant expression in 293H cells with immunoblotting for ERK/p90RSK phosphorylation; NIH-3T3 soft-agar colony-formation assay with selumetinib treatment.
Similarly, treatment of a second ECD patient with MAP2K1Q56P-mutant disease refractory to 4 lines of prior therapy led to resolution of PET-avid disease in renal (SUV 8.4), aortic (SUV 3.9), and maxillary sinus (SUV 9.5) infiltrations to background SUV within a single month of administration of the MEK inhibitor cobimetinib (Fig. 4C).
Results, section 'Therapeutic Targeting of MAP2K1- and ARAF-mutant Refractory Histiocytoses'; Discussion
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 375978)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.841. BayesDel score = 0.49396.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61068787, n = 37 times).
This variant lies in a statistically significant hotspot.