The MAP2K1 NM_002755.4:c.370C>T (NP_002746.1:p.(Pro124Ser)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61068297, n = 59 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Approved MAP2K1 functional assays and variant-specific ERK/MEK phosphorylation results support a damaging effect. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen RASopathy Variant Curation Expert Panel; ClinVar ID 375981).
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: approved MAP2K1 functional assays and variant-specific ERK/MEK phosphorylation results support a damaging effect.
Met, moderate: residue 124 falls within the VCEP-approved critical domain AA 124-134 specified for PM1.
Met at Supporting: NM_002755.4:c.370C>T is absent from both gnomAD v2.1 and v4.1, satisfying the VCEP requirement for absence from controls.
Met: REVEL 0.855 meets the VCEP missense threshold of ≥0.7 for PP3 Supporting evidence.
Not applicable: the MAP2K1 VCEP prohibits PP5 use for this VCEP.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3, PM1, PM2, and PP3 are applied, but one moderate plus three supporting criteria do not satisfy a MAP2K1 VCEP pathogenic 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: 0.855. Refer to the recorded PP3/BP4 rationale for interpretation.
3 Pathogenic · 2 Likely pathogenic. ClinVar API review status: reviewed by expert panel.
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; COSV61068297, n = 59 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 · 5 not met · 10 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the three requested consequence/length/repeat criteria, the VCEP makes PVS1 and BP3 not applicable; PM4 is not met because the variant is missense and does not change protein length.
PS2, PM6, PP1, and BS4 are not assessed because the available evidence contains no qualifying parental testing, de novo RASopathy case data, informative meioses, affected-relative segregation, or non-segregation observation.
PS3 is met at Supporting strength because the VCEP-approved MAP2K1 functional assay classes are pre-assigned PS3_Supporting and variant-specific studies report abnormal MEK/ERK pathway behavior for p.Pro124Ser.
BS3 is not applicable under the MAP2K1 VCEP specification and is pre-assigned BS3_NA in the governing functional-studies table.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 was not assessed because the available evidence does not provide VCEP-qualified RASopathy phenotype-specific case/control data or a VCEP point assignment.
PP4, PP5, and BP6 are not applicable under the MAP2K1 VCEP; BP5 is not assessed because no alternative molecular cause or point assignment is documented.
PP3 is met at Supporting strength because the VCEP's named missense predictor, REVEL, is 0.855 and meets the ≥0.7 threshold.
BP4 is not met because the VCEP's missense REVEL threshold is ≤0.3 and the observed score is 0.855.
BP7 is not applicable because the variant is missense, outside BP7's synonymous, intronic, and non-coding scope.
Population evidence supports PM2 at Supporting strength because the variant is absent from gnomAD v2.1 and v4.1.
BA1 and BS1 are not met because no gnomAD allele frequency reaches their VCEP thresholds.
BS2 is not assessed because absence from gnomAD does not provide the healthy-genotype observations or VCEP point score required for that criterion.
No criteria match.
The governing MAP2K1 VCEP functional-studies table approves MEK activation and ERK activation assays for MAP2K1 and pre-assigns each approved assay type to PS3_Supporting, with BS3_NA. Variant-specific functional evidence is present: p.Pro124Ser caused ERK1/2 phosphorylation without serum and showed transformation activity in transfected-cell assays (PMID:22197931); p.P124S induced ERK phosphorylation in a pan-cancer functional assay (PMID:32641410); and p.P124S was experimentally characterized through MEK and ERK phosphorylation assays, although signaling was RAF- and phosphorylation-dependent (PMID:29483135). The VCEP CSPEC rule states, "One approved assay." These variant-specific results support PS3 at Supporting strength, but the governing table contains no variant-specific row assigning a higher strength and the pre-assigned assay classification outranks any independent assay count.
One approved assay.
The variant encodes p.Pro124Ser, placing residue 124 within the VCEP-defined critical functional domain AA 124-134. The VCEP limits PM1 to critical, well-established domains in the supplementary table and excludes specific amino-acid-residue use under PM1; residue 124 meets the listed domain interval. The required MAP2K-Alignment.xlsx file was searched for c.370C>T, p.Pro124Ser, and p.P124S, but contains no entry for this variant; the CSPEC domain rule is sufficient for the domain assessment.
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).
PM2 is met at Supporting strength. The governing MAP2K1 VCEP rule requires that the variant be absent from controls in gnomAD. NM_002755.4:c.370C>T (NP_002746.1:p.Pro124Ser) is reported absent from gnomAD v2.1 and gnomAD v4.1. The governing rule does not specify a non-cancer or exome-only subset, so the all-comers gnomAD results are the applicable default; the available non-cancer queries are also absent.
The variant must be absent from controls (gnomAD).
NM_002755.4:c.370C>T produces the missense variant NP_002746.1:p.(Pro124Ser). The governing MAP2K1 VCEP rule specifies the missense pathway as REVEL ≥ 0.7. The local REVEL lookup reports 0.855, which meets that threshold; this supports PP3 at Supporting strength. The available SpliceAI result is not used for PP3 because the VCEP's missense pathway is satisfied by the named REVEL predictor, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The reviewed literature reports the exact MAP2K1 p.Pro124Ser/c.370 variant, but no distinct nucleotide substitution producing the same amino-acid change was identified as a previously established pathogenic variant. The VCEP PS1 rule requires the same amino-acid change as a previously established pathogenic variant regardless of nucleotide change; the available reports do not provide that qualifying distinct-nucleotide comparator.
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 applies PM4 to protein length changes caused by in-frame deletions or insertions in a non-repeat region or by stop-loss variants. NM_002755.4:c.370C>T is a missense substitution producing p.(Pro124Ser), with no protein length change; therefore PM4 is not met. The VCEP also states there are no known repetitive areas in the gene, but that does not convert a missense substitution into a PM4-eligible length-changing variant.
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... No known repetitive areas in gene. Use as described.
BA1 is not met. The governing MAP2K1 VCEP rule requires a gnomAD filtering allele frequency ≥0.05%. The variant NM_002755.4:c.370C>T (NP_002746.1:p.Pro124Ser) is absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency reaches the VCEP threshold. The governing rule does not require use of a non-cancer subset, and the available non-cancer queries are likewise reported absent.
GnomAD filtering allele frequency ≥0.05%.
BS1 is not met. The governing MAP2K1 VCEP rule requires a gnomAD filtering allele frequency ≥0.025%. The variant NM_002755.4:c.370C>T (NP_002746.1:p.Pro124Ser) is absent from gnomAD v2.1 and gnomAD v4.1, so no allele frequency reaches the VCEP threshold. The governing rule does not require use of a non-cancer subset, and the available non-cancer queries are likewise reported absent.
GnomAD filtering allele frequency ≥0.025%.
NM_002755.4:c.370C>T is a missense variant, NP_002746.1:p.(Pro124Ser), so the VCEP's missense BP4 pathway applies. That pathway requires REVEL ≤ 0.3. The local REVEL lookup reports 0.855, which is above the benign threshold; therefore BP4 is not met. The available SpliceAI result is not used for BP4 because the governing missense rule names REVEL, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≤0.3.
No case-specific documentation establishes that MAP2K1 c.370C>T (p.Pro124Ser) is de novo in a proband with confirmed maternity and paternity, and no VCEP point score can be assigned from the available evidence. The available variant-specific publications describe somatic melanoma findings and functional studies, not germline parental testing or a RASopathy proband de novo observation.
4 Points; 2 Points; 1 Point.
The MAP2K1 VCEP applies PS4 by point-based scoring for autosomal-dominant cases with phenotypic specifications, with full points for RASopathy phenotypes and reduced points for minimal phenotype information; strength thresholds are >=5 points for Strong, >=3 for Moderate, and >=1 for Supporting. The available variant-specific papers report somatic melanoma cohorts or functional studies, not affected RASopathy patients versus unaffected or population controls, and no PS4 point assignments or qualifying RASopathy phenotype cohort are available. The literature_pass.json packet has no ai_classified_papers to verify. Therefore PS4 cannot be evaluated from the available VCEP-qualified evidence; no odds ratio or confidence interval was computed because no qualifying case/control counts or matched-ancestry control frequency were reported.
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 point.
PMID:22197931 reports p.Pro124Gln at the same codon in cardio-faciocutaneous syndrome, providing a same-codon alternate residue lead. However, the available evidence does not establish p.Pro124Gln as a likely pathogenic variant under the VCEP rule, and the PM5 candidate collection contains no qualifying same-residue candidates. Therefore the required pathogenicity of the comparator cannot be evaluated from the allowed evidence.
≥2 different [likely] pathogenic residues changes at the same codon observed in ≥5 probands. ... 1 [likely] pathogenic residue change at the same codon.
No case-specific evidence establishes an assumed de novo MAP2K1 c.370C>T (p.Pro124Ser) occurrence without confirmed maternity and paternity. The available variant-specific publications describe somatic melanoma observations and functional studies, not an assumed de novo RASopathy case, so the VCEP point score cannot be assigned.
2 Points; 1 Point; 0.5 Points.
No affected relatives, family genotype-phenotype data, or informative meioses are documented for MAP2K1 c.370C>T (p.Pro124Ser). Therefore, the VCEP thresholds of at least 3, 5, or 7 informative meioses cannot be evaluated.
≥7 informative meioses; ≥5 informative meioses; ≥3 informative meioses.
The VCEP requires a gnomAD missense z score greater than 3.09 for PP2. No MAP2K1 gnomAD missense z score is present in the available case evidence, so the criterion cannot be evaluated without substituting an unapproved value or threshold.
Missense z score is >3.09 in gnomAD.
BS2 cannot be assessed from the available evidence. The governing MAP2K1 VCEP rule assigns strength using healthy homozygote or heterozygote observations: -4 points for the strong level or -1 point for the supporting level. The population records report the variant as absent from gnomAD v2.1 and v4.1, but provide no healthy-carrier, homozygote, or heterozygote observations and therefore do not establish the point score required by the VCEP.
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.
No affected family members have been evaluated for MAP2K1 c.370C>T (p.Pro124Ser), and no non-segregation observation or informative meiosis is documented. Consequently, the VCEP's single-informative-meiosis requirement for BS4 cannot be evaluated.
Requires only one informative meiosis.
The VCEP provides BP2 point thresholds of ≥ (-4), ≥ (-2), and ≥ (-1) points, but the available evidence contains no documented phase, affected-proband observation, or pathogenic/likely pathogenic variant in cis or trans from which a BP2 point value can be assigned. Somatic tumor reports do not establish germline allelic phase or inheritance.
≥ (-4) Points. ... ≥ (-2) Points. ... ≥ (-1) Point.
The MAP2K1 VCEP permits BP5 when an alternative molecular cause of RASopathy is present in a different gene, with a phenotype consistent with the expected RASopathy severity, or when a phenotype inconsistent with RASopathy is fully explained by a different causative variant. No case-level evidence documents an alternative causative variant or such a fully explained alternative phenotype for this sample. The available melanoma papers describe somatic tumor findings and do not establish the BP5 alternative molecular cause for this case. The VCEP's own strength thresholds are >=(-4) points for Strong, >=(-2) for Moderate, and >=(-1) for Supporting, but no BP5 point value is available; applying any other threshold or inferring a point score would violate the VCEP-only rule.
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 MAP2K1 VCEP marks PVS1 as not applicable. NM_002755.4:c.370C>T is a missense variant, NP_002746.1:p.(Pro124Ser), in exon 3, rather than a VCEP-defined null variant such as a nonsense, frameshift, canonical splice, initiation-codon, or exon-deletion variant.
Not applicable.
The ClinGen RASopathy Expert Panel MAP2K1 Version 2.3 specification explicitly marks PM3 as not applicable. No PM3 evidence is therefore evaluated.
Not Applicable
The MAP2K1 VCEP explicitly marks PP4 as not applicable and directs users to PS4 instead.
Not applicable, see PS4.
The MAP2K1 VCEP CSPEC marks BS3 as not applicable. The governing functional-studies table likewise pre-assigns BS3_NA for the approved MAP2K1 MEK-activation and ERK-activation assay classes. Therefore normal functional results cannot be used to apply BS3 under this VCEP framework.
Not applicable
BP1 is limited by the VCEP to truncating variants, including nonsense, frameshift, canonical splice-site, initiation-codon, whole-gene, or multi-exon deletions in genes without established loss-of-function correlation. This variant is a missense substitution, p.Pro124Ser, so it is outside the rule's named variant types.
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 MAP2K1 VCEP marks BP3 as not applicable and states that there are no known benign repetitive areas in RASopathy genes. This missense substitution is not an in-frame deletion or insertion in a repetitive region without known function.
No known benign repetitive areas in RASopathy genes.
The MAP2K1 VCEP marks BP6 as not applicable for this VCEP and states that the criterion 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.
NM_002755.4:c.370C>T is a missense variant, NP_002746.1:p.(Pro124Ser). The governing MAP2K1 VCEP BP7 rule covers synonymous variants and additionally intronic positions other than canonical splice sites or non-coding variants. A missense coding variant is outside those named variant types, so BP7 is not_applicable before splice-prediction evidence is considered.
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.
NM_002755.4:c.370C>T produces the missense variant NP_002746.1:p.(Pro124Ser). The governing MAP2K1 VCEP rule specifies the missense pathway as REVEL ≥ 0.7. The local REVEL lookup reports 0.855, which meets that threshold; this supports PP3 at Supporting strength. The available SpliceAI result is not used for PP3 because the VCEP's missense pathway is satisfied by the named REVEL predictor, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≥ 0.7. For splicing impact, predicted outcome must match disease mechanism.
NM_002755.4:c.370C>T is a missense variant, NP_002746.1:p.(Pro124Ser), so the VCEP's missense BP4 pathway applies. That pathway requires REVEL ≤ 0.3. The local REVEL lookup reports 0.855, which is above the benign threshold; therefore BP4 is not met. The available SpliceAI result is not used for BP4 because the governing missense rule names REVEL, and the same prediction is not double-counted across criteria.
For missense variants: REVEL ≤0.3.
NM_002755.4:c.370C>T is a missense variant, NP_002746.1:p.(Pro124Ser). The governing MAP2K1 VCEP BP7 rule covers synonymous variants and additionally intronic positions other than canonical splice sites or non-coding variants. A missense coding variant is outside those named variant types, so BP7 is not_applicable before splice-prediction evidence is considered.
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 = 0.855. BayesDel score = 0.223852.
5 paper records listed. 4 cited in the classification.
The paper also notes that MAP2K1 p.Pro124Ser was previously reported in the context of MEK-inhibitor resistance, while p.Pro124Gln at the same codon was described in cardio-faciocutaneous syndrome.
Location Results, “Functional and structural implications of MAP2K1 mutations”
Context Sanger sequencing of MAP2K1, MAP2K2, BRAF, and NRAS in melanoma samples; ERK phosphorylation and NIH3T3 transformation assays; melanoma-cell drug-response assays.
MEK1P124S and MEK1P124Q have slightly elevated kinase activity and cause a significant, albeit slight decrease in dabrafenib sensitivity.
Location Table 1; Results sections on positive selection of MEK1 Pro124 mutations, clinical response, and RAF-independent kinase activity; Figure 3
Context Four published melanoma cohorts; engineered BRAF-mutant SKMel28 cell assays measuring ERK phosphorylation and clonogenic survival; endogenous-mutant melanoma cell-line comparisons.
RAF-dependent MEK1 mutants (D67N, P124L and P124S), both MEK and ERK phosphorylation were decreased to trace levels in RAF-less cells.
Location Results, paragraphs describing Fig. 1B–C and Fig. 2E; Table 1 classification
Context Expression assays in 293H cells, in vitro kinase assays, and conditional RAF-knockout/RAF-less MEF cells.
Among the hotspot sites, we confirmed that MEK1 point mutants predicted to disrupt helix-A in the negative regulatory domain (F53L, Q56P, K57E/N and D67N) or distort the position of helix-C in the kinase domain (C121S, P124S/L, G128D/V, and Y130C) (Fig. 2A) were activating, consistent with the literature (2,3,25–32).
Location Results, “Pan-cancer landscape of MAP2K1 mutations,” paragraphs 2–4
Context Pan-cancer analysis of 42,434 tumors; 115 MEK1 mutants functionally evaluated by expression in HEK-293 cells and ERK-phosphorylation measurement; molecular-dynamics simulations.
Five MAP2K1 gene mutations (encodes the MEK1 kinase) were detected in either drug-resistance specimens (3 mutations; MEK1V60E, MEK1G128V, and MEK1V154I in Patients 41, 32, and 28, respectively) or pre-treatment tumors that progressed rapidly in the face of clinical RAF inhibition (2 mutations; MEK1P124S and MEK1P124L in Patients 4 and 15, respectively) (Fig. 1B).
Results, subsection “MEK1 mutations confer resistance to RAF and MEK inhibitors when expressed inducibly”
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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) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 375981)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.855. BayesDel score = 0.223852.
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; COSV61068297, n = 59 times).
This variant lies in a statistically significant hotspot.