The MAP2K1 NM_002755.4:c.171G>T (NP_002746.1:p.(Lys57Asn)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61068581, n = 36 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: The approved ERK activation assay shows increased ERK signaling for K57N, while the VCEP table pre-assigns this assay class PS3_Supporting. 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.Lys57Asn change is previously established as pathogenic and reported repeatedly in MAP2K1 studies.
Met at Supporting: the approved ERK activation assay shows increased ERK signaling for K57N, while the VCEP table pre-assigns this assay class PS3_Supporting.
Met, moderate: residue 57 lies within the VCEP-approved critical domain spanning amino acids 43-61.
Met, Supporting: the variant is absent from both default all-comers gnomAD v2.1 and v4.1, satisfying the VCEP's PM2 absence requirement.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS1 (strong) plus PM1 (moderate) satisfy Rule11 of the MAP2K1 VCEP; PS3 and PM2 provide additional supporting evidence.
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: 0.585. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Pathogenic · 1 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; COSV61068581, n = 36 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: 4 met · 4 not met · 10 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The codon/residue/domain group supports PS1 at strong strength and PM1 at moderate strength.
PM5 and PP2 remain unassessed because their required comparator and gene-level missense-z-score evidence is unavailable or incomplete.
BP1 is not applicable because the variant is missense rather than truncating or another named loss-of-function variant type.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 remains not assessed because the available variant-specific reports concern somatic cancer or somatic mosaic melorheostosis and do not provide a VCEP-scored RASopathy point assignment or a qualifying matched case-control estimate.
PP4, PP5, and BP6 are not applicable under the VCEP text; BP5 remains not assessed because no alternate molecular cause and sufficient phenotype data are available.
Only PP3, BP4, and BP7 were adjudicated under the ClinGen RASopathy Expert Panel MAP2K1 Version 2.3 specification.
The missense REVEL score of 0.585 meets neither the VCEP PP3 threshold of ≥0.7 nor the VCEP BP4 threshold of ≤0.3; BP7 is outside scope for this exonic missense variant.
No criteria match.
The variant is MAP2K1 c.171G>T, p.Lys57Asn (p.K57N). This exact amino-acid change has been previously reported and is represented in ClinVar with pathogenic submissions; the governing VCEP permits PS1 for the same amino-acid change regardless of nucleotide change and for analogous MAP2K1/MAP2K2 residue positions. The exact variant is also documented in multiple primary reports, including lung-cancer cohorts and functional studies.
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 variant is explicitly reported as MAP2K1/MEK1 K57N and c.171G>T. Multiple full-text studies show abnormal pathway function: increased ERK phosphorylation and downstream p90RSK signaling in transfected 293H cells, IL-3-independent Ba/F3 growth, RAF-regulated ERK activity, and increased MEK–ERK signaling in affected osteoblasts. The governing VCEP functional-studies table lists the MEK Activation Assay and ERK Activation Assay as approved pathway-specific assays for MAP2K1, but its MAP2K1 ERK-assay entry assigns the approved assay class PS3_Supporting; the table does not provide a variant-specific pre-assigned moderate code or document two distinct approved assay classes for this variant. Therefore PS3 is applied at Supporting strength under the VCEP rule for one approved assay. The reported soft-agar, transformation, proliferation, mineralization, and treatment-response findings are corroborating functional observations but are not counted as additional approved assay classes.
One approved assay.
MAP2K1 p.Lys57Asn affects residue 57, which is within the VCEP-defined critical functional domain spanning amino acids 43-61. The VCEP limits PM1 to the critical domains in its supplementary table and states that it is not for specific residues; residue 57 therefore qualifies through the domain route. The required MAP2K-Alignment.xlsx full-text file was searched for c.171G>T, p.Lys57Asn, and p.K57N; no matching variant entry was found, but the governing CSPEC domain definition supplies the applicable interval.
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 requires PM2 Supporting when the variant is absent from controls in gnomAD. The variant is reported absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records, satisfying the VCEP's absence requirement; the VCEP provides no additional ancestry, prevalence, penetrance, or frequency threshold for PM2.
The variant must be absent from controls (gnomAD).
The variant is a missense substitution, NP_002746.1:p.(Lys57Asn), so the VCEP's missense PP3 path applies and names REVEL with a cutoff of ≥0.7. The available REVEL score is 0.585, below that cutoff, so PP3 is not met. SpliceAI reports a maximum delta score of 0.006 and no significant splice impact; this does not provide a predicted splice outcome matching the disease mechanism under the VCEP's separate splicing-impact clause, and it is not used to double-count the missense prediction.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The MAP2K1 NM_002755.4:c.171G>T (p.Lys57Asn) variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records. Its observed filtering allele frequency is therefore 0 in both reported datasets, below the VCEP threshold of 0.05% (0.0005), so BA1 is not met.
GnomAD filtering allele frequency ≥0.05%.
The MAP2K1 NM_002755.4:c.171G>T (p.Lys57Asn) variant is absent from the default all-comers gnomAD v2.1 and gnomAD v4.1 records. Its observed filtering allele frequency is therefore 0 in both reported datasets, below the VCEP threshold of 0.025% (0.00025), so BS1 is not met.
GnomAD filtering allele frequency ≥0.025%.
The variant is a missense substitution, NP_002746.1:p.(Lys57Asn), so the VCEP's missense BP4 path applies and names REVEL with a cutoff of ≤0.3. The available REVEL score is 0.585, above that cutoff, so BP4 is not met. The absence of a predicted splice effect is not used for BP4 because the VCEP's BP4 rule for this situation is the missense REVEL rule, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≤0.3.
The VCEP assigns PS2 strength by de novo evidence points, with thresholds of 1 point for Moderate, 2 points for Strong, and 4 points for Very Strong. The available case evidence contains no confirmed de novo observation, proband-parent genotypes, parental testing results, or phenotype-consistent de novo assessment for MAP2K1 c.171G>T; therefore no PS2 points can be assigned.
4 Points. ... 2 Points. ... 1 Point.
The VCEP makes PS4 applicable using point-based scoring for autosomal-dominant RASopathy cases, with full points for RASopathy phenotypes and reduced points for minimal phenotypic information. The available literature verifies variant observations in somatic lung cancer and melorheostosis, not an affected RASopathy cohort with a VCEP PS4 point assignment. PMID:29643386 reports p.K57N in affected bone from four melorheostosis patients and absence from matched unaffected bone and blood, but this is a somatic mosaic phenotype rather than the VCEP's RASopathy PS4 context; PMID:18632602 reports 2/93 and 2/207 lung tumors, and PMID:25351745 reports 20/26 MEK1-mutated lung cancers, without matched unaffected-control counts for this variant. These observations do not provide the VCEP-required PS4 point score, and the available counts cannot be converted into a qualifying VCEP PS4 assessment. The VCEP rule's case-control note states that OR/RR >5.0 with a confidence interval excluding 1.0 supports the original PS4 path, but no suitable matched case-control dataset for the VCEP disease context is available here.
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)). ... The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. ... ≥5 points. ... ≥3 points. ... ≥1 points.
The VCEP requires at least one different likely pathogenic residue change at the same codon for PM5 at moderate strength. The available comparator collection reports zero same-residue candidates, but its search also ended with an HTTP 429 error; therefore the available evidence does not reliably establish that no qualifying comparator exists.
1 \[likely\] pathogenic residue change at the same codon.
The VCEP assigns PM6 strength by de novo evidence points, with thresholds of 0.5 points for Supporting, 1 point for Moderate, and 2 points for Strong. No unconfirmed de novo observation, proband-parent genotype information, parental testing, or phenotype-consistent de novo evidence is available for MAP2K1 c.171G>T; therefore PM6 cannot be assessed.
2 Points. ... 1 Point. ... 0.5 Points.
The VCEP requires at least 3 informative meioses for PP1 Supporting, at least 5 for Moderate, or at least 7 for Strong. No informative meioses, affected relatives, segregation results, or family genotypes are reported for MAP2K1 c.171G>T, so PP1 cannot be assessed.
≥7 informative meioses. ... ≥5 informative meioses. ... ≥3 informative meioses.
The VCEP requires a MAP2K1 missense z score greater than 3.09 in gnomAD. The case evidence documents that the variant is absent from gnomAD, but it does not provide the gene-level missense z score, so this criterion cannot be evaluated under the VCEP rule.
Missense z score is >3.09 in gnomAD.
The VCEP specifies BS2 through phenotype-based point scoring for healthy homozygous or heterozygous individuals, including reduced points for apparently unaffected heterozygotes. The available evidence reports only that the variant is absent from gnomAD; it provides no qualifying healthy individual, zygosity, phenotype, age, or point assignment. BS2 therefore 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.
The VCEP states that BS4 at Strong strength requires one informative meiosis. No informative meiosis, unaffected carrier relative, non-segregation result, or family genotype is available for MAP2K1 c.171G>T; therefore BS4 cannot be assessed.
Requires only one informative meiosis.
BP2 is applicable in the MAP2K1 VCEP framework, but the available case evidence does not document parental or family testing, phase, affected probands, or a pathogenic MAP2K1 variant in cis or trans. The VCEP's BP2 instruction requires points for an alternative molecular cause of a RASopathy in the same gene, with phenotype consistent with the expected severity; that evidence is not available here. Therefore BP2 cannot be assessed without phase-resolved familial or proband-level evidence.
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.
The VCEP permits BP5 when an alternative molecular cause in a different gene explains the phenotype, or when a phenotype inconsistent with RASopathy is fully explained by another causative variant, with point-based strength adjustment. The available case materials do not provide a patient-level alternate pathogenic variant in another gene, phase or diagnostic result, and phenotype information sufficient to evaluate this rule. No BP5-specific numeric value is available; therefore no comparison or strength assignment can be made.
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 ClinGen RASopathy VCEP MAP2K1 Version 2.3 CSPEC entry explicitly marks PVS1 as not applicable. The case variant is NM_002755.4:c.171G>T, a missense substitution producing NP_002746.1:p.(Lys57Asn) in exon 2, not a loss-of-function consequence requiring NMD, exon-importance, or protein-length assessment.
Not Applicable
PM3 is not applicable under the ClinGen RASopathy Expert Panel MAP2K1 specification. The VCEP explicitly marks PM3 as not applicable, so no recessive trans-phase evidence is evaluated for this autosomal-dominant RASopathy framework.
Not applicable.
The VCEP PM4 entry states that the rule is used as described and specifies the absence of known repetitive areas in the gene. Under that deferred PM4 framework, this criterion concerns protein-length changes; NM_002755.4:c.171G>T is a missense substitution, p.(Lys57Asn), with no protein-length change, so PM4 is outside the criterion's variant type.
No known repetitive areas in gene. Use as described.
The MAP2K1 VCEP explicitly marks PP4 as not applicable and directs users to PS4. No independent PP4 assessment is permitted under this governing framework.
Not applicable, see PS4.
The MAP2K1 VCEP explicitly excludes PP5 because it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The ClinVar and literature reports therefore cannot be used to assign PP5 under this framework.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The MAP2K1 Version 2.3 CSPEC marks BS3 as Not applicable. The VCEP-approved functional-studies table likewise assigns BS3_NA for the approved assay entries relevant to MAP2K1; benign functional evidence therefore cannot be applied under this VCEP specification.
Not applicable.
The variant is missense, whereas the MAP2K1 VCEP limits BP1 to truncating or other loss-of-function variant types in genes without established LOF correlation to disease. This c.171G>T substitution is not truncating, splice-site, initiation-codon, whole-gene, or multi-exon loss of function.
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 ClinGen RASopathy VCEP MAP2K1 Version 2.3 CSPEC entry explicitly marks BP3 as not applicable. The variant is a missense substitution, NM_002755.4:c.171G>T, p.(Lys57Asn), rather than a protein-length-altering in-frame indel in a repetitive region.
Not Applicable
The MAP2K1 VCEP explicitly marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Benign reports cannot be assigned BP6 under this framework.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7 covers synonymous variants and, by the VCEP's explicit extension, intronic positions except canonical splice sites or non-coding variants. NM_002755.4:c.171G>T is an exonic missense variant encoding p.(Lys57Asn), so it is outside BP7's scope and BP7 is not applicable.
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 variant is a missense substitution, NP_002746.1:p.(Lys57Asn), so the VCEP's missense PP3 path applies and names REVEL with a cutoff of ≥0.7. The available REVEL score is 0.585, below that cutoff, so PP3 is not met. SpliceAI reports a maximum delta score of 0.006 and no significant splice impact; this does not provide a predicted splice outcome matching the disease mechanism under the VCEP's separate splicing-impact clause, and it is not used to double-count the missense prediction.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
The variant is a missense substitution, NP_002746.1:p.(Lys57Asn), so the VCEP's missense BP4 path applies and names REVEL with a cutoff of ≤0.3. The available REVEL score is 0.585, above that cutoff, so BP4 is not met. The absence of a predicted splice effect is not used for BP4 because the VCEP's BP4 rule for this situation is the missense REVEL rule, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≤0.3.
BP7 covers synonymous variants and, by the VCEP's explicit extension, intronic positions except canonical splice sites or non-coding variants. NM_002755.4:c.171G>T is an exonic missense variant encoding p.(Lys57Asn), so it is outside BP7's scope and BP7 is not applicable.
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 = 0.01). REVEL score = 0.585. BayesDel score = -0.144321.
7 paper records listed. 5 cited in the classification.
The remaining two confirmed somatic mutations involved the same G→T transversion in exon 2 at nucleotide 171 of MEK1, found initially in 2 of 93 independent lung tumor samples (of which, 89, including the two with MEK1 changes, were of adenocarcinoma histology; Fig. 1A). This change substitutes asparagine for lysine at position 57.
Location Results, paragraphs 4–6
Context Somatic mutation screening of 261 NSCLC specimens plus additional NSCLC samples and cell lines; transient 293T and stable Ba/F3 functional assays.
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).
Location Results, Spectrum of MEK1 mutations
Context MEK1 mutation screening in 5330 lung adenocarcinoma patients with ERK/p90RSK phosphorylation and NIH-3T3 soft-agar assays.
A MAP2K1K57N mutation was noted from WES of peri-renal lesions from a 53-year-old ECD patient with progressive disease following treatment with both interferon-alpha and anakinra, who was symptomatic by way of inflammatory ascites and renal failure.
Location Results, Therapeutic Targeting of MAP2K1- and ARAF-mutant Refractory Histiocytoses
Context Whole-exome sequencing and droplet digital PCR in an ECD lesion, clinical trametinib treatment, and mutant-expression assays.
RAF-regulated MEK1 mutants (F53L, C121S, K57N and Q56P) have an intermediate effect on signaling when expressed in these cells
Location Results, RAF-depleted-cell signaling experiments
Context Cell signaling, recombinant-protein kinase, transformation, xenograft, and MEK-inhibitor assays for recurrent MEK1 mutants.
This approach revealed three additional patients with MAP2K1 p.K57N mutations at lower mutant allele frequencies
Location Results, amplicon sequencing and ddPCR validation; Table 1; Figures 4–5
Context Cohort of 15 melorheostosis patients assessed by sequencing, ddPCR, osteoblast signaling, proliferation, mineralization, and marker-expression assays.
These are only predictions, however, and their use in sequence interpretation should be implemented carefully. It is not recommended that these predictions be used as the sole source of evidence to make a clinical assertion.
Section: Computational (in silico) predictive programs, page 5
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 (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 223140)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.585. BayesDel score = -0.144321.
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; COSV61068581, n = 36 times).
This variant lies in a statistically significant hotspot.