About MAP2K1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MAP2K1 c.158T>C, p.(Phe53Ser)
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 ClinGen MAP2K1 VCEP v2.3.0. 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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Supporting
PS3 · supporting
Published functional studies of MAP2K1 cardio-facio-cutaneous syndrome variants including F53S showed abnormal downstream MAPK signaling, and the RASopathy VCEP materials recognize MEK/ERK activation assays as approved assay types. This supports a damaging gain-of-function effect for this missense variant at supporting strength.
PM1Moderate
PM1 · moderate
This missense variant affects MAP2K1 codon 53, which lies within the RASopathy VCEP-defined critical functional region spanning amino acids 43-61. This is within the specified PM1 domain and supports pathogenicity at moderate strength.
PM2Supporting
PM2 · supporting
This variant was not identified in gnomAD v2.1 or gnomAD v4.1. Under the RASopathy MAP2K1 framework, absence from controls supports PM2 at supporting strength.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the MAP2K1 VCEP PP3 threshold of 0.7, SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00, and the BayesDel score is 0.464442, which is also consistent with a damaging missense prediction rather than a benign effect.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MAP2K1 VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 4 not met · 11 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MAP2K1 c.158T>C (p.Phe53Ser) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar, including an expert panel submission classifying it as likely pathogenic.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
Published functional studies of cardio-facio-cutaneous syndrome-associated MAP2K1 variants including F53S showed abnormal MAPK-pathway signaling, and the RASopathy VCEP recognizes MEK and ERK activation assays as approved functional assay types, supporting a damaging gain-of-function effect.
Computational findings support a deleterious missense effect, with REVEL 0.938 above the VCEP PP3 threshold of 0.7, BayesDel 0.464442 in a damaging direction, and no predicted splice alteration by SpliceAI with a maximum delta score of 0.00.
No criteria match.
Met · 5
PS3 SupportingPublished functional studies of MAP2K1 cardio-facio-cutaneous syndrome variants including F53S showed abnormal downstream MAPK signaling, and the RASopathy VCEP materials recognize MEK/ERK activation assays as approved assay types. This supports a damaging gain-of-function effect for this missense variant at supporting strength. Details ▾Hide ▴
Rule
One approved assay = PS3 Supporting; two or more different approved assays = PS3 Moderate
Evidence considered
- VCEP-approved assay categories include MEK activation and ERK activation assays for MAP2K1
- PMID:17981815 specifically includes F53S among CFC-associated MEK1 variants with abnormal ERK signaling behavior
- PMID:18413255 reports increased MEK-pathway activity for germline MEK variants associated with CFC syndrome
Still missing
- Variant-level assay details were not fully extracted from the primary figures/tables to determine whether moderate-strength PS3 could be justified.
Sources
PM1 ModerateThis missense variant affects MAP2K1 codon 53, which lies within the RASopathy VCEP-defined critical functional region spanning amino acids 43-61. This is within the specified PM1 domain and supports pathogenicity at moderate strength. Details ▾Hide ▴
Rule
MAP2K1 PM1 applies to amino acids 43-61 and 124-134
Evidence considered
- VCEP PM1 domain for MAP2K1 includes amino acids 43-61
- p.Phe53Ser falls within that domain
Sources
PM2 SupportingThis variant was not identified in gnomAD v2.1 or gnomAD v4.1. Under the RASopathy MAP2K1 framework, absence from controls supports PM2 at supporting strength. Details ▾Hide ▴
Rule
Variant must be absent from controls (gnomAD)
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the MAP2K1 VCEP PP3 threshold of 0.7, SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00, and the BayesDel score is 0.464442, which is also consistent with a damaging missense prediction rather than a benign effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7; for splicing, predicted outcome must match disease mechanism
Evidence considered
- REVEL 0.938
- SpliceAI max delta 0.00
- BayesDel 0.464442
Sources
Not met · 4 · evaluated, threshold not reached
BA1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the MAP2K1 VCEP BA1 threshold of at least 0.05%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.05%
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold >=0.05%
Sources
BS1 This variant was absent from gnomAD v2.1 and gnomAD v4.1, so it is below the MAP2K1 VCEP BS1 threshold of at least 0.025%. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency >=0.025%
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 threshold >=0.025%
Sources
BS3 Available functional evidence does not show a normal or benign MAP2K1 effect. Instead, published studies support abnormal downstream signaling consistent with a damaging gain-of-function effect. Details ▾Hide ▴
Rule
Benign functional evidence requires well-established studies showing no damaging effect
Evidence considered
- Approved functional assay categories are available for MAP2K1
- Published studies support abnormal signaling rather than normal function
Sources
BP4 Computational findings do not support a benign interpretation. The REVEL score is 0.938, which is above the MAP2K1 VCEP benign threshold of 0.3, SpliceAI shows no splice disruption with a maximum delta score of 0.00, and the BayesDel score of 0.464442 is not consistent with a benign missense prediction. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3
Evidence considered
- REVEL 0.938
- BP4 threshold for missense REVEL <=0.3
- SpliceAI max delta 0.00
- BayesDel 0.464442
Sources
Not assessed · 11 · no assessment recorded
PS1 No directly verified evidence was identified showing a different nucleotide change that produces the same MAP2K1 p.Phe53Ser amino acid substitution and is already established as pathogenic. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
Evidence considered
- VCEP allows PS1 for the same amino acid change regardless of nucleotide change
- Available records confirm the current p.Phe53Ser variant but do not document an alternate nucleotide change causing the same protein change
Still missing
- A codon-level review for alternate nucleotide changes encoding p.Phe53Ser would be needed to fully resolve PS1.
Sources
PS2 Published disease literature for MAP2K1-related cardio-facio-cutaneous syndrome describes de novo missense variants at the gene level, but no case-level evidence was directly verified here confirming this exact variant as de novo with both maternity and paternity established. Details ▾Hide ▴
Rule
RASopathy point-based de novo evidence with confirmed maternity and paternity
Evidence considered
- RASopathy VCEP uses point-based de novo scoring
- PMID:16439621 reports de novo MAPK-pathway missense variants in cardio-facio-cutaneous syndrome
Still missing
- Patient-level parental testing details for the exact variant were not directly verified.
- A full-text review would be needed to assign de novo points under the RASopathy framework.
Sources
PS4 This variant has been reported in ClinVar and in published cardio-facio-cutaneous syndrome literature, but the number of independent affected probands needed for RASopathy PS4 point scoring was not directly verified from the available records. Details ▾Hide ▴
Rule
RASopathy point-based affected proband evidence
Evidence considered
- ClinVar contains an expert panel classification for the variant
- Multiple publications in the retrieved set discuss MAP2K1-associated CFC syndrome and include this variant in the literature trail
Still missing
- The exact number of qualifying unrelated affected individuals with this variant was not confirmed.
- PS4 point assignment under the VCEP framework requires case-level counting.
Sources
PM5 No directly verified codon-level evidence was identified here showing a different pathogenic or likely pathogenic amino acid change at MAP2K1 codon 53 that would support PM5. Details ▾Hide ▴
Rule
One pathogenic residue change at same codon = PM5 Moderate; two or more different changes in at least five probands = PM5 Strong
Evidence considered
- VCEP allows PM5 for pathogenic missense changes at the same codon or analogous MAP2K1/MAP2K2 residues
- Available records confirm the current variant but do not directly document other qualifying codon-53 substitutions
Still missing
- A codon-specific review across MAP2K1 and analogous MAP2K2 residues would be needed to resolve PM5.
Sources
PM6 Gene-level literature supports that cardio-facio-cutaneous syndrome variants in this pathway are often de novo, but no directly verified report was identified here showing this exact variant as assumed de novo without confirmed parentage so PM6 points cannot be assigned confidently. Details ▾Hide ▴
Rule
RASopathy point-based assumed de novo evidence
Evidence considered
- RASopathy VCEP uses point-based PM6 scoring for assumed de novo events
- PMID:16439621 describes de novo MAPK-pathway variants in CFC syndrome
Still missing
- Exact wording for an assumed de novo occurrence of this variant was not directly verified.
Sources
PP1 No segregation data were identified for this variant, so informative meioses required for PP1 were not available. Details ▾Hide ▴
Rule
Supporting at at least 3 informative meioses, moderate at at least 5, strong at at least 7
Evidence considered
- No pedigree-based segregation evidence was retrieved
Still missing
- Family-based segregation data were not identified.
Sources
PP2 The RASopathy MAP2K1 framework allows PP2 when the gnomAD missense z score is greater than 3.09, but that gene-level z score was not directly available in the reviewed materials. Details ▾Hide ▴
Rule
Missense z score >3.09 in gnomAD
Evidence considered
- VCEP PP2 threshold is missense z score >3.09
Still missing
- The MAP2K1 missense z score was not directly verified.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals that would allow point-based BS2 scoring. Details ▾Hide ▴
Rule
Point-based unaffected individual evidence
Evidence considered
- Variant absent from gnomAD
- No unaffected carrier observations were retrieved
Still missing
- Unaffected carrier data were not identified.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
Requires at least one informative meiosis showing lack of segregation
Evidence considered
- No informative family non-segregation evidence was retrieved
Still missing
- Family data demonstrating lack of segregation were not identified.
Sources
BP2 No phase data or alternative molecular explanation was identified that would support BP2 scoring. Details ▾Hide ▴
Rule
Point-based BP2 scoring under the RASopathy framework
Evidence considered
- No phase-based evidence was retrieved
Still missing
- No confirmed trans/cis observations with another relevant variant were identified.
Sources
BP5 No alternative molecular diagnosis or clearly sufficient competing explanation for the phenotype was identified. Details ▾Hide ▴
Rule
Point-based alternative molecular explanation evidence
Evidence considered
- No alternate molecular explanation was retrieved
Still missing
- No independently established alternate molecular cause was identified.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the RASopathy MAP2K1 framework does not apply PVS1 for this gene/variant type. The generic null-variant scaffold also indicates that this variant does not fall into a nonsense, frameshift, or canonical splice-site category. Details ▾Hide ▴
Rule
MAP2K1 RASopathy VCEP: PVS1 not applicable
Evidence considered
- MAP2K1 VCEP marks PVS1 as not applicable
- p.Phe53Ser is a missense change rather than a predicted loss-of-function null variant
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this RASopathy MAP2K1 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MAP2K1 VCEP marks PM3 as not applicable
Sources
PM4 N/AThis variant is a missense substitution and does not change protein length or produce an in-frame insertion or deletion, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes such as in-frame indels or stop-loss
Evidence considered
- p.Phe53Ser is a missense substitution
Sources
PP4 N/APP4 is not applicable in this RASopathy MAP2K1 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MAP2K1 VCEP marks PP4 as not applicable
Sources
BP1 N/ABP1 in this RASopathy framework is intended for truncating loss-of-function variants in genes primarily associated with gain-of-function disease. This variant is a missense change, so BP1 does not apply. Details ▾Hide ▴
Rule
Truncating LOF variant in a gene primarily associated with missense/GOF disease
Evidence considered
- p.Phe53Ser is a missense variant
- BP1 guidance in this framework addresses truncating variants
Sources
BP3 N/ABP3 is not applicable in this RASopathy MAP2K1 framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MAP2K1 VCEP marks BP3 as not applicable
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP
Evidence considered
- MAP2K1 VCEP marks BP6 as not applicable
Sources
BP7 N/ABP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or relevant non-coding variant with no splice impact
Evidence considered
- p.Phe53Ser is a missense variant
- SpliceAI max delta 0.00 does not change the missense nature of the variant
Sources
Identifiers
- Gene
- MAP2K1
- Transcript
- NM_002755.4
- Coding (HGVS c.)
- NM_002755.4:c.158T>C
- Protein (HGVS p.)
- NP_002746.1:p.(Phe53Ser)
- GRCh38
- chr15:66435104 T>C
- GRCh37
- chr15:66727442 T>C
Gene diagram
Every interpreted variant in MAP2K1, mapped onto the exon structure of NM_002755.4. Select a row to find it on the plot.
MAP2K1NM_002755.4
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 MAP2K1
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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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious missense effect. The REVEL score is 0.938, which is above the MAP2K1 VCEP PP3 threshold of 0.7, SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.00, and the BayesDel score is 0.464442, which is also consistent with a damaging missense prediction rather than a benign effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7; for splicing, predicted outcome must match disease mechanism
Evidence considered
- REVEL 0.938
- SpliceAI max delta 0.00
- BayesDel 0.464442
Sources
BP4 Computational findings do not support a benign interpretation. The REVEL score is 0.938, which is above the MAP2K1 VCEP benign threshold of 0.3, SpliceAI shows no splice disruption with a maximum delta score of 0.00, and the BayesDel score of 0.464442 is not consistent with a benign missense prediction. Details ▾Hide ▴
Rule
For missense variants: REVEL <= 0.3
Evidence considered
- REVEL 0.938
- BP4 threshold for missense REVEL <=0.3
- SpliceAI max delta 0.00
- BayesDel 0.464442
Sources
BP7 N/ABP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or relevant non-coding variant with no splice impact
Evidence considered
- p.Phe53Ser is a missense variant
- SpliceAI max delta 0.00 does not change the missense nature of the variant
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.938. BayesDel score = 0.464442.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243115
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/13350/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-66727442-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-66435104-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002755.4%3Ac.158T…
- OncoKB ↗www.oncokb.org/gene/MAP2K1/F53S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=107839244
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.938. BayesDel score = 0.464442.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105128267, n = 2 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.