About MAP2K1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MAP2K1 c.146G>A, p.(Arg49His)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS2Moderate
PS2 · moderate
A confirmed de novo occurrence of NM_002755.3:c.146G>A (p.Arg49His) was reported in a patient with cardio-facio-cutaneous syndrome; both parents were tested and the variant was absent in both, satisfying 1 point under the RASopathy VCEP PS2 point-based scoring system (Moderate strength).
PM1Moderate
PM1 · moderate
The variant affects amino acid position 49 (p.Arg49His), which lies within the VCEP-designated critical functional domain spanning amino acids 43-61 of MAP2K1. This region is specified in the RASopathy VCEP supplementary table as a well-established functional domain eligible for PM1 at Moderate strength.
PP3Supporting
PP3 · supporting
The REVEL score for NM_002755.3:c.146G>A (p.Arg49His) is 0.707, which meets the RASopathy VCEP PP3 threshold of REVEL ≥ 0.7 for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico evidence derives entirely from the REVEL missense prediction.
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: PS2 moderate, PM1 moderate, PP3 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
5 / 1,614,100 alleles
gnomAD v4.1: 5 / 1,614,100 alleles. Recorded AF 3.0977e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97836e-06; MAF= 0.00040%, 1/251360 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61070158, n = 4 times).
Cancer Hotspots
This variant does not lie 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.
26 criteria with recorded statuses: 3 met · 14 not met · 1 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
NM_002755.3:c.146G>A (p.Arg49His) in MAP2K1 is a missense variant located within the VCEP-designated critical functional domain spanning amino acids 43-61, satisfying PM1 at Moderate strength.
A confirmed de novo occurrence of this variant was reported in a patient with cardio-facio-cutaneous syndrome, with both maternity and paternity confirmed, satisfying PS2 at Moderate strength (1 point under VCEP scoring).
The REVEL in silico score is 0.707, meeting the VCEP PP3 threshold of ≥0.7 for missense variants at Supporting strength.
This variant is present at extremely low frequency in gnomAD (AF ~0.0004%), far below both the BA1 (≥0.05%) and BS1 (≥0.025%) thresholds, and present in only 1 allele in v2.1 and 5 alleles in v4.1.
No alternative pathogenic missense change at codon 49 was identified (PM5 not met), and the variant is not absent from gnomAD controls (PM2 not met per VCEP requirement for complete absence).
PP2 (missense constraint z-score) remains unassessed pending gnomAD constraint data retrieval. If the MAP2K1 missense z-score exceeds 3.09, PP2_Supporting would also be met.
ClinVar lists this variant as Uncertain significance (1 submitter, SCV003504233, Labcorp Genetics). No expert panel classification is available.
Under the RASopathy VCEP v2.3.0 combination rules, the current met criteria (PM1_Moderate + PS2_Moderate + PP3_Supporting) do not satisfy any rule for Likely Pathogenic or Pathogenic classification. If PP2_Supporting is also met, Rule14 (2 Moderate + ≥2 Supporting) would be satisfied, yielding Likely Pathogenic.
No criteria match.
Met · 3
PS2 ModerateA confirmed de novo occurrence of NM_002755.3:c.146G>A (p.Arg49His) was reported in a patient with cardio-facio-cutaneous syndrome; both parents were tested and the variant was absent in both, satisfying 1 point under the RASopathy VCEP PS2 point-based scoring system (Moderate strength). Details ▾Hide ▴
Evidence considered
- Exploratory evidence retrieval identified Rodriguez-Viciana et al. (2006
- DOI:10.1038/ng1746
- PMID:16439621) reporting a de novo germline c.146G>A mutation in a CFC patient with both maternity and paternity confirmed. This qualifies for 1 point = PS2_Moderate under VCEP rules.
Still missing
- Full-text verification of PMID:16439621 not available in the case publications directory
- de novo assertion was identified by secondary exploratory search and should be confirmed against the primary publication.
Sources
PM1 ModerateThe variant affects amino acid position 49 (p.Arg49His), which lies within the VCEP-designated critical functional domain spanning amino acids 43-61 of MAP2K1. This region is specified in the RASopathy VCEP supplementary table as a well-established functional domain eligible for PM1 at Moderate strength. Details ▾Hide ▴
Evidence considered
- RASopathy VCEP v2.3.0 PM1 rule: 'Applicable only to critical and well-established functional domains available in the supplementary table (AA 43-61
- AA 124-134).' Residue 49 falls within AA 43-61.
Sources
PP3 SupportingThe REVEL score for NM_002755.3:c.146G>A (p.Arg49His) is 0.707, which meets the RASopathy VCEP PP3 threshold of REVEL ≥ 0.7 for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico evidence derives entirely from the REVEL missense prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.707 (≥0.7 threshold met). SpliceAI max delta = 0.00 (no splice impact). BayesDel = 0.139 (not incorporated in VCEP PP3 rule).
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (p.Arg49His) from a different nucleotide change has been identified in ClinVar or the literature for MAP2K1 or the analogous MAP2K2 residue. Details ▾Hide ▴
PS3 No evidence that p.Arg49His has been evaluated in VCEP-approved functional assays with a demonstrated damaging effect. The variant is not listed among validated pathogenic controls in the RASopathy VCEP Approved Functional Studies spreadsheet. OncoKB annotates the variant as Likely Neutral, which is inconsistent with a damaging functional effect. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional assays spreadsheet does not include p.Arg49His as a tested variant. OncoKB classifies R49H as Likely Neutral. PMID:32641410 is a functional benchmarking study of MAP2K1/2 variants but variant-specific data for R49H could not be verified from the available abstract/screenshot.
Still missing
- Full-text review of PMID:32641410 needed to determine whether p.Arg49His was directly assayed and what functional result was obtained.
Sources
PS4 Insufficient case-control evidence to apply PS4 under the VCEP point-based system. The variant is reported in ClinVar as Uncertain significance by a single clinical laboratory (SCV003504233, Labcorp Genetics). No curated case-control study demonstrating statistically significant enrichment of this variant in RASopathy patients versus controls is available. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submission
- VUS classification. gnomAD: extremely rare (AF ~4e-6) but no formal case-control comparison available.
Still missing
- Need a systematic case count from published RASopathy cohorts or a dedicated case-control study to apply PS4 point-based scoring.
Sources
PM2 The RASopathy VCEP PM2 rule requires the variant to be absent from gnomAD controls. NM_002755.3:c.146G>A is present in gnomAD v2.1 at an allele frequency of 3.98e-6 (1/251,360 alleles) and in gnomAD v4.1 at 3.10e-6 (5/1,614,100 alleles). Because the variant is observed in population controls, PM2_Supporting cannot be applied. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1 allele
- AF=3.98e-6
- gnomAD v4.1: 5 alleles
- AF=3.10e-6
- gnomAD-Canada: absent.
Sources
PM5 No alternative pathogenic or likely pathogenic missense variant at codon 49 of MAP2K1 (or the analogous MAP2K2 residue) was identified. The VCEP PM5 rule requires at least one [likely] pathogenic residue change at the same codon for Moderate strength; no such comparator variant was found in ClinVar or the literature. Details ▾Hide ▴
PM6 The single de novo observation of c.146G>A (PMID:16439621) had both maternity and paternity confirmed, qualifying it as PS2 rather than PM6. No separate de novo events lacking full parental confirmation were identified for this variant. Under the SVI point-based system, a given de novo event is scored under either PS2 or PM6, not both. Details ▾Hide ▴
Evidence considered
- The known de novo event has both parents tested (PS2). No additional assumed-de-novo events identified.
Sources
PP1 No evidence of co-segregation of c.146G>A in multiple affected family members was identified. Cardio-facio-cutaneous syndrome is typically caused by de novo mutations, and familial cases with this variant have not been reported. Details ▾Hide ▴
Evidence considered
- Exploratory search found no co-segregation reports. CFC syndrome typically presents as de novo disease.
BA1 The RASopathy VCEP BA1 threshold is a gnomAD filtering allele frequency ≥ 0.05%. This variant has an allele frequency of approximately 0.0004% (3.98e-6 in v2.1, 3.10e-6 in v4.1), far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=3.98e-6 (0.0004%)
- v4.1 AF=3.10e-6 (0.00031%). Both far below 0.05% BA1 threshold.
Sources
BS1 The RASopathy VCEP BS1 threshold is a gnomAD filtering allele frequency ≥ 0.025%. This variant has an allele frequency of approximately 0.0004%, far below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=3.98e-6
- v4.1 AF=3.10e-6. Both far below 0.025% BS1 threshold.
Sources
BS2 No evidence that NM_002755.3:c.146G>A has been observed in a healthy adult individual without a RASopathy phenotype. The single allele observed in gnomAD v2.1 (Admixed American population) lacks phenotypic annotation and cannot be confirmed as a healthy carrier. Details ▾Hide ▴
Evidence considered
- One carrier in gnomAD v2.1 without phenotypic data. No published reports of healthy adult carriers.
Still missing
- Phenotypic data for the gnomAD carrier(s) is unavailable
- cannot confirm or exclude healthy status.
Sources
BS4 No evidence of non-segregation of c.146G>A in affected family members has been reported. Given that CFC syndrome is typically caused by de novo mutations, non-segregation data is not expected but its absence precludes application of BS4. Details ▾Hide ▴
Evidence considered
- No reports of an affected family member lacking the variant. Exploratory search found no non-segregation evidence.
BP2 No evidence that c.146G>A has been observed in trans with another pathogenic MAP2K1 variant or that an alternative molecular cause in MAP2K1 explains the phenotype in a patient carrying this variant. No evidence satisfying the VCEP BP2 point-based scoring system was identified. Details ▾Hide ▴
Evidence considered
- No reports of this variant in trans/cis with a pathogenic MAP2K1 variant. Exploratory search found no BP2 evidence.
Sources
BP4 The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤ 0.3. The REVEL score for p.Arg49His is 0.707, which exceeds the BP4 threshold and instead meets PP3 (REVEL ≥ 0.7). Details ▾Hide ▴
BP5 No evidence of an alternative molecular cause in a different gene that fully explains the RASopathy phenotype in a patient carrying c.146G>A. No evidence satisfying the VCEP BP5 point-based scoring criteria was identified. Details ▾Hide ▴
Evidence considered
- No reports of patients with c.146G>A who have an alternative molecular diagnosis. Exploratory search found no BP5 evidence.
Sources
Not assessed · 1 · no assessment recorded
PP2 The RASopathy VCEP PP2 rule requires a missense z-score >3.09 in gnomAD for MAP2K1. The gnomAD missense constraint metric (z-score) was not retrieved during evidence collection and could not be verified. Details ▾Hide ▴
Evidence considered
- VCEP specifies PP2_Supporting if MAP2K1 missense z-score >3.09 in gnomAD. This value was not available in the evidence brief or prefetch data.
Still missing
- Retrieve MAP2K1 missense constraint z-score from gnomAD to determine PP2 applicability.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is not applicable per the ClinGen RASopathy VCEP v2.3.0. This is a missense variant (c.146G>A, p.Arg49His), not a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion). Details ▾Hide ▴
Evidence considered
- VCEP declares PVS1 not applicable for this gene/disease framework.
Sources
PP4 VCEPPP4 is not applicable per the ClinGen RASopathy VCEP v2.3.0. The VCEP directs users to PS4 for phenotype-based evidence instead. Details ▾Hide ▴
Evidence considered
- VCEP declares PP4 not applicable
- phenotype specificity is addressed through PS4.
Sources
PP5 VCEPPP5 is not for use under the ClinGen RASopathy VCEP v2.3.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable per the ClinGen RASopathy VCEP v2.3.0. The VCEP does not define strength rules for BS3 in this framework, consistent with the panel's assessment that well-established functional studies showing no damaging effect are not sufficient for benign classification in RASopathy genes. Details ▾Hide ▴
BP1 N/ABP1 under the RASopathy VCEP applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, or multi-exon deletion) in genes where loss of function is not an established disease mechanism. NM_002755.3:c.146G>A is a missense variant (p.Arg49His), not a truncating variant. Details ▾Hide ▴
Evidence considered
- VCEP BP1 rule is specific to truncating variants
- this is a missense substitution.
Sources
BP6 VCEPBP6 is not for use under the ClinGen RASopathy VCEP v2.3.0, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_002755.3:c.146G>A is a missense variant (p.Arg49His), not a synonymous variant. Details ▾Hide ▴
PS5 N/APS5 is not defined in the ClinGen RASopathy VCEP v2.3.0 criteria specifications. This criterion (reputable source reports variant as pathogenic without available evidence) is not for use under this VCEP framework, consistent with the VCEP's treatment of PP5 and BP6. Details ▾Hide ▴
Identifiers
- Gene
- MAP2K1
- Transcript
- NM_002755.3
- Coding (HGVS c.)
- NM_002755.3:c.146G>A
- Protein (HGVS p.)
- NP_002746.1:p.(Arg49His)
- GRCh38
- chr15:66435092 G>A
- GRCh37
- chr15:66727430 G>A
- ClinVar
- 2185892
- COSMIC
- COSV61070158
Gene diagram
Every interpreted variant in MAP2K1, mapped onto the exon structure of NM_002755.3. Select a row to find it on the plot.
MAP2K1NM_002755.3
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 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
5 / 1,614,100 alleles
AF 3.1e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
1 / 251,360 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,614,100 alleles · 0 hom · FAF 7.9e-07
| Admixed American1 / 60,010 | 1.7e-05 |
| European (non-Finnish)4 / 1,179,980 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,360 alleles · 0 hom
| Admixed American1 / 34,588 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.0977e-06; MAF= 0.00031%, 5/1614100 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97836e-06; MAF= 0.00040%, 1/251360 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.707
- BayesDel
- 0.139
How the predictions were used
PP3 SupportingThe REVEL score for NM_002755.3:c.146G>A (p.Arg49His) is 0.707, which meets the RASopathy VCEP PP3 threshold of REVEL ≥ 0.7 for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), so the in silico evidence derives entirely from the REVEL missense prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.707 (≥0.7 threshold met). SpliceAI max delta = 0.00 (no splice impact). BayesDel = 0.139 (not incorporated in VCEP PP3 rule).
Sources
BP4 The RASopathy VCEP BP4 threshold for missense variants is REVEL ≤ 0.3. The REVEL score for p.Arg49His is 0.707, which exceeds the BP4 threshold and instead meets PP3 (REVEL ≥ 0.7). Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_002755.3:c.146G>A is a missense variant (p.Arg49His), not a synonymous variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.707. BayesDel score = 0.13946.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 32641410 ↗Leveraging Systematic Functional Analysis to Benchmark an In Silico Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
5 / 1,614,100 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
1 Uncertain significance
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/2185892/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-66727430-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-66435092-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002755.3%3Ac.146G…
- OncoKB ↗www.oncokb.org/gene/MAP2K1/R49H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128937703
- 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= 3.0977e-06; MAF= 0.00031%, 5/1614100 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66639e-05; MAF= 0.00167%, 1/60010 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97836e-06; MAF= 0.00040%, 1/251360 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89118e-05; MAF= 0.00289%, 1/34588 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2185892)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.707. BayesDel score = 0.13946.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61070158, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.