About MAP2K4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MAP2K4 c.400C>T, p.(Arg134Trp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM1Moderate
PM1 · moderate
p.Arg134Trp (R134W) lies at a well-established mutational hotspot in MAP2K4. It is identified as one of two COSMIC hotspot mutations (R134W and S184L) and is located in a statistically significant hotspot domain (β3-αC loop), as confirmed by cancerhotspots.org and PMID:33101607.
PM2Moderate
PM2 · moderate
NM_003010.3:c.400C>T is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency of 6.2×10⁻⁷ (1/1,613,378 alleles; highest subpopulation NFE AF=8.5×10⁻⁷). This frequency is well below the 0.1% threshold for PM2.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate; combination = 2 moderate, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,613,378 alleles
gnomAD v4.1: 1 / 1,613,378 alleles. Recorded AF 6.19818e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 19 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
MAP2K4 c.400C>T (p.Arg134Trp) is a missense variant located at a well-established mutational hotspot (PM1_moderate) in the β3-αC loop of the kinase domain. It is the most frequent MKK4 mutation catalogued in COSMIC and lies within a statistically significant hotspot domain as defined by cancerhotspots.org.
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is observed at an extremely low frequency in gnomAD v4.1 (1/1,613,378 alleles; AF=6.2×10⁻⁷), meeting the PM2 criterion for very low population frequency (PM2_moderate).
Computational in silico predictors are indeterminate: REVEL (0.475) and BayesDel (0.247) fall below established pathogenic thresholds, and SpliceAI predicts no splice alteration. PP3 is not met.
Molecular dynamics simulations (PMID:33101607) demonstrate that p.Arg134Trp introduces a TRP134-TRP134 π-π interaction that distorts the N-lobe dimer interface of autoinhibited MKK4, but this computational evidence does not independently meet PS3 criteria for well-established functional evidence.
The variant is absent from ClinVar and no clinical laboratory or expert panel classification is available. No de novo, segregation, case-control, or experimental functional data were identified for this variant.
Two pathogenic criteria of moderate strength are met (PM1 and PM2). Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two moderate criteria are insufficient to reach a Likely Pathogenic classification, which requires at least three moderate criteria or two moderate plus two supporting criteria. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM1 Moderatep.Arg134Trp (R134W) lies at a well-established mutational hotspot in MAP2K4. It is identified as one of two COSMIC hotspot mutations (R134W and S184L) and is located in a statistically significant hotspot domain (β3-αC loop), as confirmed by cancerhotspots.org and PMID:33101607. Details ▾Hide ▴
Evidence considered
- Statistically significant hotspot at residue 134
- R134W is the most frequent MKK4 mutation in COSMIC (PMID:33101607)
- cancerhotspots.org also confirms hotspot significance at this residue
Sources
PM2 ModerateNM_003010.3:c.400C>T is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency of 6.2×10⁻⁷ (1/1,613,378 alleles; highest subpopulation NFE AF=8.5×10⁻⁷). This frequency is well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 613
- 378 alleles (AF=6.2e-7)
- gnomAD-Canada: absent
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No prior observation of a different nucleotide change at the same amino acid (p.Arg134) with a pathogenic classification has been identified in ClinVar or published literature. Details ▾Hide ▴
PS2 No de novo observation with confirmed maternity and paternity has been identified for NM_003010.3:c.400C>T. Details ▾Hide ▴
Evidence considered
- No de novo data identified in any reviewed source
Still missing
- No segregation or parent-of-origin data available
PS3 No well-established in vitro or in vivo functional assay data exist for p.Arg134Trp. PMID:33101607 provides molecular dynamics simulations showing altered dimer interface interactions but this is computational modeling, not a validated functional assay. OncoKB annotation of 'Likely Loss-of-function' is a curated inference, not primary functional evidence meeting PS3 threshold. Details ▾Hide ▴
Evidence considered
- MD simulations show R134W alters N-lobe dimer contacts and introduces Trp134-Trp134 π-π interactions (PMID:33101607)
- OncoKB curated label=Likely Oncogenic
- Likely Loss-of-function
Still missing
- No experimental functional assay (e.g.
- kinase activity
- luciferase reporter
- phosphorylation assays) for p.Arg134Trp
Sources
PS4 No case-control or aggregate cohort data comparing variant prevalence in affected individuals versus controls have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No cohort enrichment data available
Still missing
- No affected-vs-control prevalence data
PM6 No de novo observation (assumed de novo without confirmation of maternity/paternity) has been identified for NM_003010.3:c.400C>T. Details ▾Hide ▴
Evidence considered
- No de novo data available
Still missing
- No parent-of-origin or de novo testing data
PP1 No co-segregation data in affected family members have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies available
PP3 In silico predictors do not support a deleterious effect: REVEL score is 0.475 (below 0.5 pathogenic threshold), BayesDel score is 0.247 (below ~0.27 pathogenic threshold), and SpliceAI max delta score is 0.00 indicating no predicted splice impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.475 (<0.5)
- BayesDel=0.247 (<0.27)
- SpliceAI max delta=0.00
Sources
PP4 No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for a MAP2K4-related disorder. Details ▾Hide ▴
Evidence considered
- No phenotypic data available
Still missing
- Patient phenotype and family history not provided
PP5 No reputable source (diagnostic laboratory, expert panel) has reported this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no external pathogenic classification identified
Sources
BA1 The variant has a maximum population allele frequency of 8.5×10⁻⁷ in gnomAD v4.1 (NFE), far below the BA1 threshold of >1%. Details ▾Hide ▴
BS1 The variant has a total allele frequency of 6.2×10⁻⁷ in gnomAD v4.1, far below the BS1 threshold of >0.3%. Details ▾Hide ▴
BS2 No observation of this variant in healthy adult individuals in the context of a fully penetrant disorder expected to manifest at an early age has been identified. Details ▾Hide ▴
Evidence considered
- No relevant healthy-adult observation data for a disorder with complete penetrance
Still missing
- No phenotype or penetrance data available
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect have been identified. PMID:33101607 is a computational MD simulation study and does not constitute an experimental functional assay. Details ▾Hide ▴
Evidence considered
- PMID:33101607 reports computational simulations
- not experimental functional data
Still missing
- No experimental functional studies for p.Arg134Trp
Sources
BS4 No segregation data in affected families are available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation data
BP1 BP1 applies when missense variants occur in a gene where primarily truncating variants cause disease. MAP2K4 has well-characterized pathogenic missense mutations at known hotspots (including p.Arg134 and p.Ser184), indicating that missense variants are a recognized disease mechanism, not only truncating variants. Details ▾Hide ▴
Evidence considered
- MAP2K4 has established missense pathogenic hotspots (R134W
- S184L)
- missense is a known disease mechanism
Sources
BP4 Multiple lines of computational evidence do not confidently suggest no impact. REVEL score is 0.475 (borderline, just below 0.5 pathogenic threshold), BayesDel is 0.247 (below 0.27 pathogenic threshold but not clearly benign), and SpliceAI delta is 0.00. The aggregate in silico evidence is indeterminate rather than supportive of a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL=0.475 (borderline)
- BayesDel=0.247 (indeterminate)
- SpliceAI max delta=0.00 (no splice impact)
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been identified. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis data available
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 No reputable source has independently reported this variant as pathogenic; absent from ClinVar and no diagnostic laboratory classification identified. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP2 Insufficient data to determine whether MAP2K4 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. HCI prior data are unavailable for MAP2K4. Details ▾Hide ▴
Evidence considered
- HCI prior not available for MAP2K4
- insufficient gene-level missense constraint data
Still missing
- No gene-level missense constraint score (HCI prior) for MAP2K4
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical ±1/2 splice); NM_003010.3:c.400C>T is a missense variant (p.Arg134Trp) and does not fall into any default generic PVS1 null-variant bucket per PMC6185798. Details ▾Hide ▴
Evidence considered
- Missense substitution
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
PM3 N/APM3 applies to variants observed in trans with a pathogenic variant for recessive disorders; no trans-configuration data available and MAP2K4-associated disorders are not established as recessive. Details ▾Hide ▴
Evidence considered
- No trans-phase data
- MAP2K4 disease association is not established as recessive
PM4 N/APM4 applies to protein-length altering variants (in-frame indels, stop-loss, initiation codon); NM_003010.3:c.400C>T is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a protein-length altering variant
PM5 N/ANo same-residue comparator variant with a pathogenic classification has been identified at p.Arg134 to support PM5 application; automated PM5 candidate harvesting returned no eligible candidates. Details ▾Hide ▴
Evidence considered
- No same-residue P/LP comparator variant identified in ClinVar
Sources
pm5_candidates
BP2 N/ABP2 requires observation in trans with a pathogenic variant in a fully penetrant dominant disorder, which requires specific genotypic and phase data not available for this variant. Details ▾Hide ▴
Evidence considered
- No trans-phase data available
BP3 N/ABP3 applies to in-frame indels in repetitive regions; NM_003010.3:c.400C>T is a missense substitution. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not an in-frame indel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_003010.3:c.400C>T is a missense substitution (p.Arg134Trp). Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant
Identifiers
- Gene
- MAP2K4
- Transcript
- NM_003010.3
- Coding (HGVS c.)
- NM_003010.3:c.400C>T
- Protein (HGVS p.)
- NP_003001.1:p.(Arg134Trp)
- GRCh38
- chr17:12095581 C>T
- GRCh37
- chr17:11998898 C>T
Gene diagram
Every interpreted variant in MAP2K4, mapped onto the exon structure of NM_003010.3. Select a row to find it on the plot.
MAP2K4NM_003010.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MAP2K4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,613,378 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,378 alleles · 0 hom
| European (non-Finnish)1 / 1,179,796 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19818e-07; MAF= 0.00006%, 1/1613378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47604e-07; MAF= 0.00008%, 1/1179796 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.475
- BayesDel
- 0.247
How the predictions were used
PP3 In silico predictors do not support a deleterious effect: REVEL score is 0.475 (below 0.5 pathogenic threshold), BayesDel score is 0.247 (below ~0.27 pathogenic threshold), and SpliceAI max delta score is 0.00 indicating no predicted splice impact. Details ▾Hide ▴
Evidence considered
- REVEL=0.475 (<0.5)
- BayesDel=0.247 (<0.27)
- SpliceAI max delta=0.00
Sources
BP4 Multiple lines of computational evidence do not confidently suggest no impact. REVEL score is 0.475 (borderline, just below 0.5 pathogenic threshold), BayesDel is 0.247 (below 0.27 pathogenic threshold but not clearly benign), and SpliceAI delta is 0.00. The aggregate in silico evidence is indeterminate rather than supportive of a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL=0.475 (borderline)
- BayesDel=0.247 (indeterminate)
- SpliceAI max delta=0.00 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_003010.3:c.400C>T is a missense substitution (p.Arg134Trp). Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.475. BayesDel score = 0.246892.
2 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 33101607 ↗The autoinhibited state of MKK4: Phosphorylation, putative dimerization and R134W mutant studied by molecular dynamics simulations.Studied the conformational dynamics of autoinhibited MKK4 by microsecond-timescale all-atom MD simulations, including the R134W mutant. In the unphosphorylated homodimer, R134W introduces a π-π stacking interaction between TRP134 residues of opposing subunits that is absent in wild-type and distorts the N-lobe dimer interface. The mutation does not alter secondary structure but increases the angle variation between the αC-helix and activation segment helix, indicating altered dimer stability. The study is purely computational; no experimental functional assay (kinase activity, phosphorylation) was performed for R134W.→ PM1 Names this variant
Source detail
The most frequent MKK4 mutation R134W, where an arginine residue is replaced with a tryptophan, is located in the loop between β3-sheet and αC-helix. However, no functional data of the R134W mutation exist to date and its effect on MKK4's function is unclear.
Location Title; Introduction (para 2); Results section 3.2; Figures 5-7; Discussion
Context All-atom molecular dynamics simulations (40 μs total); OPLS3/OPLS3e force field; Desmond MD engine; in silico only
Other recorded publications
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PMID 22722193 ↗Whole-genome analysis informs breast cancer response to aromatase inhibition.Reports MAP2K4 as a significantly mutated gene in luminal breast cancer, identifying missense (S184L) and splice-region mutations in two tumors. MAP2K4 mutations were mutually exclusive with MAP3K1 mutations. NM_003010.3:c.400C>T (p.Arg134Trp) was not specifically identified or discussed in this paper.Does not name this variant
Quoted passage
of interest, a missense (S184L) and a splice-region mutation (e2+3 likely affecting splicing) in MAP2K4 were observed in two tumours with no MAP3K1 mutation
Results section; Fig. 2; Supplementary Table 5
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,378 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_003010.3%3Ac.400C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-11998898-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-12095581-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-12095581-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003010.3%3Ac.400C…
- OncoKB ↗www.oncokb.org/gene/MAP2K4/R134W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MAP2K4+c.400C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19818e-07; MAF= 0.00006%, 1/1613378 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47604e-07; MAF= 0.00008%, 1/1179796 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.475. BayesDel score = 0.246892.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.