The MAP2K1 NM_002755.4:c.607G>A (NP_002746.1:p.(Glu203Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61068654, n = 40 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Variant-specific studies showed increased ERK phosphorylation or kinase activity, while the VCEP table preassigns PS3_Supporting for MAP2K1 approved MEK and ERK assays. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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 at Supporting: variant-specific studies showed increased ERK phosphorylation or kinase activity, while the VCEP table preassigns PS3_Supporting for MAP2K1 approved MEK and ERK assays.
Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP requirement that it be absent from gnomAD controls.
Met at Moderate: PMID:22197931 reports the alternate missense change p.Glu203Gln at the same codon in an individual with cardiofaciocutaneous syndrome.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 (supporting), PM2 (supporting), and PM5 (moderate) do not satisfy any MAP2K1 VCEP pathogenic or benign combination rule.
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: 0.621. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Likely 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; COSV61068654, n = 40 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: 3 met · 6 not met · 9 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
None of PS2, PM6, PP1, or BS4 is assessed because the available evidence lacks auditable proband-parent testing, family segregation, informative meioses, and non-segregation data.
Functional evidence supports PS3 at Supporting strength under the VCEP's pre-assigned MAP2K1 assay code.
BS3 is not applicable under the MAP2K1 VCEP specification.
Within the requested group, PP4, PP5, and BP6 are excluded by the VCEP; PS4 lacks qualifying germline RASopathy case-control or point-scored evidence; BP5 lacks an alternative molecular cause and point assignment.
Somatic melanoma and tumor studies reporting E203K were reviewed but were not substituted for the VCEP's germline RASopathy phenotype and case-control requirements.
The VCEP computational criteria are evaluated on their own named paths without substituting other predictors or double-counting splice and protein predictions.
PP3 and BP4 are not met because the VCEP-specified REVEL score is 0.621, while BP7 is not applicable to this missense variant.
No criteria match.
PS3 is met at Supporting strength. The governing VCEP functional-studies table lists MEK Activation Assay and ERK Activation Assay as approved assay classes for MAP2K1, with the pre-assigned proposed strength "PS3_Supporting; BS3_NA". Variant-specific functional publications report increased MEK1 kinase activity or ERK phosphorylation for p.E203K: PMID:25351745 observed increased ERK phosphorylation in transiently transfected 293H cells; PMID:29483135 observed higher p-ERK than wild-type MEK1 in 293H cells; PMID:32641410 validated E203K as ERK-activating; PMID:18456719 summarizes increased basal kinase activity and increased ERK1/2 phosphorylation; and PMID:22197931 reports constitutive ERK1/2 phosphorylation and transformation activity. The VCEP's pre-assigned Supporting code governs over independently upgrading strength from the number of reports or assay types. The requested c.607G>A notation was not found in the named VCEP spreadsheet, nor were p.Glu203Lys or p.E203K; the evidence therefore supports the approved assay-class designation but is not a variant-specific pre-assignment in that spreadsheet.
One approved assay.
The governing MAP2K1 VCEP rule assigns PM2 at supporting strength when the variant is absent from controls in gnomAD. NM_002755.4:c.607G>A (p.Glu203Lys) was absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, satisfying the VCEP's absence requirement. The available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records were also absent; the VCEP does not specify a non-cancer-only source for PM2.
The variant must be absent from controls (gnomAD).
The VCEP assigns PM5 Moderate for one likely pathogenic residue change at the same codon. PMID:22197931 reports p.Glu203Gln at MAP2K1 codon 203 in an individual with cardiofaciocutaneous syndrome, a RAS/MAPK disorder caused by germline mutations. This is a different missense change from p.Glu203Lys and is the available same-codon clinical comparator; the paper does not independently label E203Q as likely pathogenic, so human review is retained.
1 [likely] pathogenic residue change at the same codon.
The VCEP requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. The reviewed literature reports the requested p.Glu203Lys variant itself (also written c.610G>A in PMID:22197931), but no distinct nucleotide change producing p.Glu203Lys was identified; p.Glu203Gln is a different amino acid change and belongs under PM5, not PS1.
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 VCEP limits PM1 to critical and well-established functional domains in AA 43-61 and AA 124-134, and excludes specific amino acid residues covered by PM5. The variant is p.Glu203Lys (residue 203), outside both approved ranges. vcep_materials.json has no domain_tables entry for MAP2K1. The governing MAP2K-Alignment.xlsx text was searched for c.607G>A, p.Glu203Lys, and p.E203K with no matching entry.
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 VCEP applies PP3 to missense variants using REVEL >= 0.7, or to splicing impact when the predicted outcome matches the disease mechanism. This is a missense variant, NM_002755.4:c.607G>A (p.Glu203Lys), and the governing missense predictor is REVEL; the available REVEL score is 0.621, below the VCEP cutoff. SpliceAI predicts a low maximum delta score of 0.023, but that predictor is not the named predictor for the VCEP missense path and is not used to establish PP3 here.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The governing MAP2K1 VCEP rule requires a gnomAD filtering allele frequency of at least 0.05% for BA1. NM_002755.4:c.607G>A (p.Glu203Lys) was absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no observed allele frequency reaches 0.05%. The available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records were also absent, but the VCEP does not specify a non-cancer-only source for BA1.
GnomAD filtering allele frequency ≥0.05%.
The governing MAP2K1 VCEP rule requires a gnomAD filtering allele frequency of at least 0.025% for BS1. NM_002755.4:c.607G>A (p.Glu203Lys) was absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, so no observed allele frequency reaches 0.025%. The available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer records were also absent, but the VCEP does not specify a non-cancer-only source for BS1.
GnomAD filtering allele frequency ≥0.025%.
The VCEP's BP4 missense path requires REVEL <= 0.3. This variant is missense, NM_002755.4:c.607G>A (p.Glu203Lys), and its REVEL score is 0.621, which is above the VCEP cutoff; therefore BP4 is applicable but not met. The low SpliceAI score is not used for this missense path because the VCEP names REVEL for missense variants.
For missense variants: REVEL ≤0.3.
The VCEP assigns PS2 by de novo evidence points (1, 2, or 4 points), but the available record does not document a proband-level de novo observation with parental testing, phenotype details, or an auditable point assignment. ClinVar records the variant origin as de novo, but this is a submission-level origin field without the underlying parental-testing evidence needed to apply the VCEP point scale.
4 Points. 2 Points. 1 Point.
The VCEP makes PS4 applicable and requires point-based scoring for autosomal-dominant RASopathy cases, with Supporting at ≥1 point, Moderate at ≥3 points, and Strong at ≥5 points. The reviewed literature does not provide qualifying germline RASopathy case-control counts, a matched-control comparison, or VCEP PS4 point assignments for NM_002755.4:c.607G>A (p.Glu203Lys). PMID:18456719 discusses E203K only as prior functional work and reports a different patient variant, E203Q; PMID:22197931 and PMID:32641410 report somatic cancer observations rather than RASopathy case-control evidence; PMID:23652378 is unrelated to MAP2K1, and PMID:24121147 was not available as readable full text. Therefore the VCEP PS4 score cannot be evaluated without substituting non-VCEP evidence or assumptions.
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 point.
The VCEP provides PM6 point thresholds of 0.5, 1, or 2 points, but the available record does not document an assumed de novo event with parental testing, a proband phenotype, or sufficient case-level details to assign any PM6 points. The ClinVar origin field alone is not enough to determine the VCEP strength.
2 Points. 1 Point. 0.5 Points.
The VCEP requires at least 3 informative meioses for Supporting, at least 5 for Moderate, or at least 7 for Strong PP1. No variant-positive affected relatives, family structure, segregation results, or informative meioses are documented for this case.
≥7 informative meioses. ≥5 informative meioses. ≥3 informative meioses.
The VCEP requires a gnomAD missense z score greater than 3.09. The available case evidence provides no MAP2K1 missense z score, so this criterion cannot be evaluated under the VCEP rule.
Missense z score is >3.09 in gnomAD.
The governing MAP2K1 VCEP makes BS2 applicable through point-based scoring based on healthy homozygote or heterozygote individuals, with reduced points for apparently unaffected heterozygous individuals and application to parent or sibling samples during clinical family evaluations. The available evidence contains no qualifying healthy individual observation with genotype, zygosity, age, penetrance, and phenotype information, so neither the −4-point strong path nor the −1-point supporting path can be evaluated.
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.
The VCEP permits BS4 at Strong strength when there is one informative meiosis. No affected relative who lacks the variant, informative meiosis, or other non-segregation result is documented, so the criterion cannot be evaluated.
Requires only one informative meiosis.
The MAP2K1 VCEP allows BP2 when there is an alternative molecular cause of a RASopathy in the same gene and the phenotype is consistent with the expected severity of the RASopathy, with strength determined by the VCEP point thresholds. The available case evidence does not document a second pathogenic or likely pathogenic MAP2K1 variant, its phase in cis or trans with NM_002755.4:c.607G>A, or an alternative same-gene molecular cause; therefore BP2 cannot be evaluated.
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.
BP5 is applicable under the VCEP only when an alternative molecular cause of a RASopathy in a different gene, or a different fully explanatory cause for an inconsistent phenotype, is documented and assigned VCEP points. The available case evidence contains no documented alternative causative variant or VCEP BP5 point score for this patient. The applicable thresholds are ≥(-4) points for Strong, ≥(-2) points for Moderate, and ≥(-1) point for Supporting, but no point value is available to evaluate.
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.
Not applicable under the MAP2K1 RASopathy VCEP specification. The VCEP entry explicitly marks PVS1 as not applicable, and the variant is a missense substitution, NM_002755.4:c.607G>A (NP_002746.1:p.(Glu203Lys)), rather than one of the null variant classes listed in the VCEP's original ACMG summary: nonsense, frameshift, canonical splice-site, initiation-codon, or single/multi-exon deletion. Therefore, no PVS1 strength is assigned; NMD, exon importance, and protein-length-loss considerations do not create a PVS1 path under this VCEP rule.
Not applicable.
The MAP2K1 VCEP specifies PM3 as not applicable. The VCEP describes the underlying ACMG/AMP concept as evidence for a recessive disorder when the variant is detected in trans with a pathogenic variant, but MAP2K1 RASopathy is governed here as an autosomal dominant disorder and the VCEP explicitly marks PM3 not applicable.
Not applicable.
Not applicable to this variant under the VCEP PM4 rule. PM4 is restricted to protein-length changes caused by in-frame deletions/insertions in a non-repeat region or by stop-loss variants. NM_002755.4:c.607G>A is a missense substitution producing p.(Glu203Lys), with no in-frame insertion, in-frame deletion, stop-loss event, or protein-length change. The VCEP also specifies that PM4 at moderate strength requires no known repetitive areas in the gene, but that condition cannot convert this missense substitution into a qualifying PM4 variant type.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
The MAP2K1 VCEP explicitly marks PP4 as not applicable and directs evaluators to PS4 instead. No independent PP4 assertion is permitted under this VCEP specification.
Not applicable, see PS4.
The MAP2K1 VCEP explicitly marks PP5 as not applicable for this VCEP and states that the criterion is not for use. Literature or ClinVar pathogenic classifications therefore cannot be converted into PP5 under the governing specification.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BS3 is not applicable under the MAP2K1 VCEP specification. The CSPEC entry explicitly marks BS3 as "Not applicable", and the governing functional-studies table assigns BS3_NA for the approved MAP2K1 MEK and ERK assay classes. The available variant-specific functional evidence is concordantly activating or damaging rather than evidence of normal protein function or splicing.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The VCEP limits BP1 to truncating variants, including nonsense, frameshift, canonical splice-site, initiation-codon, whole-gene, or multi-exon deletion variants in genes without established loss-of-function correlation. NM_002755.4:c.607G>A is a missense variant producing p.Glu203Lys, so BP1 does not apply.
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.
Not applicable under the MAP2K1 RASopathy VCEP specification. The VCEP explicitly marks BP3 as not applicable and states that there are no known benign repetitive areas in RASopathy genes. In addition, this variant is a missense substitution, c.607G>A (p.(Glu203Lys)), not an in-frame deletion or insertion in a repetitive region without a known function, which is the original ACMG/AMP variant context quoted by the VCEP.
No known benign repetitive areas in RASopathy genes.
The MAP2K1 VCEP explicitly marks BP6 as not applicable for this VCEP and states that the criterion is not for use. A benign report from a reputable source therefore cannot be converted into BP6 under this governing specification.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7 covers synonymous variants and, under the VCEP's extension, intronic positions except canonical splice sites or non-coding variants, with no predicted splice impact and a non-highly-conserved nucleotide. This variant is a missense coding substitution, NM_002755.4:c.607G>A (p.Glu203Lys), so it lies outside BP7 scope regardless of the available low SpliceAI 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 applies PP3 to missense variants using REVEL >= 0.7, or to splicing impact when the predicted outcome matches the disease mechanism. This is a missense variant, NM_002755.4:c.607G>A (p.Glu203Lys), and the governing missense predictor is REVEL; the available REVEL score is 0.621, below the VCEP cutoff. SpliceAI predicts a low maximum delta score of 0.023, but that predictor is not the named predictor for the VCEP missense path and is not used to establish PP3 here.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The VCEP's BP4 missense path requires REVEL <= 0.3. This variant is missense, NM_002755.4:c.607G>A (p.Glu203Lys), and its REVEL score is 0.621, which is above the VCEP cutoff; therefore BP4 is applicable but not met. The low SpliceAI score is not used for this missense path because the VCEP names REVEL for missense variants.
For missense variants: REVEL ≤0.3.
BP7 covers synonymous variants and, under the VCEP's extension, intronic positions except canonical splice sites or non-coding variants, with no predicted splice impact and a non-highly-conserved nucleotide. This variant is a missense coding substitution, NM_002755.4:c.607G>A (p.Glu203Lys), so it lies outside BP7 scope regardless of the available low SpliceAI 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 = 0.02). REVEL score = 0.621. BayesDel score = 0.227552.
7 paper records listed. 5 cited in the classification.
Two mutations were novel: MEK1 E203Q and MEK2 F57L.
Location Abstract, Results
Context Comprehensive mutation analysis of BRAF, KRAS, MEK1, MEK2, and SOS1 in 31 unrelated patients without PTPN11 mutations, including patients with cardio-facio-cutaneous syndrome.
Of note, a mutation affecting the same codon (p.Glu203Gln) of MAP2K1 was observed in an individual with cardiofaciocutaneous (CFC) syndrome, a rare genetic disorder caused by germline mutations in genes encoding components of the RAS-MAPK pathway13.
Location Results, paragraph beginning 'In addition, the BRAF mutations coexisted'
Context Exome sequencing and Sanger sequencing of melanoma samples, with functional ERK phosphorylation and transformation assays; the same-codon E203Q observation is a clinical report cited in the discussion of MAP2K1 mutations.
Western blot analysis demonstrated increased kinase activity in all mutants, except for the D67N. ERK phosphorylation levels in the D67N mutant did not vary significantly from the wild-type (Figure 3A&B).
Location Results, ‘Functional characterization of MEK1 mutants,’ paragraph 1; Figure 3A&B
Context In-vitro functional assay using transiently transfected human embryonic kidney 293H cells; MEK1 mutant kinase activity was assessed by Western blot analysis of phosphorylated ERK and p90RSK.
Some mutants induced p-ERK more profoundly than pMEK (C121S, L177M, E203K, F53L, ΔF53–Q58, Q56P, K57E, K57N and ΔE51–Q58) (Fig. 1B).
Location Results, paragraph 1; Fig. 1B and Fig. 1D
Context Functional characterization of 17 recurrent tumor-associated MEK1 mutants expressed in 293H cells, including p-ERK/p-MEK immunoblot assays and S218A/S222A phosphorylation-site substitution experiments.
MEK1 E203K (n=26), the lone hotspot peak in the distal kinase domain, also validated as ERK-activating, consistent with prior studies.
Location Results, ‘Pan-cancer landscape of MAP2K1 mutations,’ paragraph 3; MD simulation paragraph
Context Somatic mutation analysis of 42,434 tumors; MEK1 mutant expression in HEK cells with ERK phosphorylation measured by western blot; 100-ns molecular-dynamics simulation of MEK1 structure and T-loop conformation.
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 Likely pathogenic (2 clinical laboratories). (ClinVarID = 375982)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.621. BayesDel score = 0.227552.
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; COSV61068654, n = 40 times).
This variant lies in a statistically significant hotspot.