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.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.2 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.3 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 0.00.4
Final classification
VUS
PS3PM1PM2PP3PP5
MAP2K1
c.158T>C
p.Phe53Ser
This variant
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.
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.
Classification rationale
PS3PM1PM2PP3PP5
VUS
MAP2K1 c.158T>C
PS3 + PM1 + PM2 + PP3 + PP5
→
VUS
3
vcep_svi_rasopathy_vcep_v2_approved_functional_studiesPMID:17981815 ↗PMID:18413255 ↗
4
revelbayesdelspliceai ↗cspec ↗
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.
Gene diagram
· NM_002755.4 · variants mapped to exon structure
MAP2K1
NM_002755.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
review
Pathogenic
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.
VCEP-approved assay categories include MEK activation and ERK activation assays for MAP2K1PMID:17981815 specifically includes F53S among CFC-associated MEK1 variants with abnormal ERK signaling behaviorPMID:18413255 reports increased MEK-pathway activity for germline MEK variants associated with CFC syndrome
PM1
moderate
Pathogenic
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.
VCEP PM1 domain for MAP2K1 includes amino acids 43-61p.Phe53Ser falls within that domain
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1Absent from gnomAD v4.1
PP3
supporting
Pathogenic
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.
REVEL 0.938SpliceAI max delta 0.00BayesDel 0.464442
Assessed · not applied
· 4 not met · 11 not assessed
Pathogenic
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.
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.
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.
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.
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.
PP1
No segregation data were identified for this variant, so informative meioses required for PP1 were not available.
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.
Benign
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%.
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%.
BS2
No evidence was identified showing this variant in unaffected individuals that would allow point-based BS2 scoring.
BS3
Available functional evidence does not show a normal or benign MAP2K1 effect.
BS4
No non-segregation data were identified for this variant.
BP2
No phase data or alternative molecular explanation was identified that would support BP2 scoring.
BP4
Computational findings do not support a benign interpretation.
BP5
No alternative molecular diagnosis or clearly sufficient competing explanation for the phenotype was identified.
N/A · 8
PVS1 · PM3 · PM4 · PP4 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Likely Oncogenic
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 in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105128267, n = 2 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to ME
Found
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
Applied to
→PS3
supporting
Biochemical characterization of novel germline BRAF and MEK mutations in cardio-
Found
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
Applied to
→PS3
supporting
Sources & reference links