Variant classification summary

NM_002755.4:c.158T>C

MAP2K1 · NP_002746.1:p.(Phe53Ser) · NM_002755.4

GRCh37: chr15:66727442 T>C · GRCh38: chr15:66435104 T>C

Gene: MAP2K1 Transcript: NM_002755.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting PP5 supporting

Variant details

Gene

MAP2K1

Transcript

NM_002755.4

Protein

NP_002746.1:p.(Phe53Ser)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.

3

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.

4

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.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K1 Version 2.3.0 v2.3.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	cspec pvs1_variant_assessment
PS1	Not assessed	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.	cspec clinvar
PS2	Not assessed	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.	cspec PMID:16439621
PS3	Met	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_svi_rasopathy_vcep_v2_approved_functional_studies PMID:17981815 PMID:18413255
PS4	Not assessed	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.	cspec clinvar PMID:16439621 PMID:17981815 PMID:18413255 PMID:18039235 PMID:21062266 PMID:20301365
PM1	Met	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.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable in this RASopathy MAP2K1 framework.	cspec
PM4	N/A	This variant is a missense substitution and does not change protein length or produce an in-frame insertion or deletion, so PM4 does not apply.	cspec
PM5	Not assessed	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.	cspec clinvar
PM6	Not assessed	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.	cspec PMID:16439621
PP1	Not assessed	No segregation data were identified for this variant, so informative meioses required for PP1 were not available.	cspec
PP2	Not assessed	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.	cspec
PP3	Met	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.	cspec revel spliceai bayesdel
PP4	N/A	PP4 is not applicable in this RASopathy MAP2K1 framework.	cspec
PP5	Met	Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.	cspec clinvar
BA1	Not met	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%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in unaffected individuals that would allow point-based BS2 scoring.	cspec gnomad_v2 gnomad_v4
BS3	Not met	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.	vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:17981815 PMID:18413255
BS4	Not assessed	No non-segregation data were identified for this variant.	cspec
BP1	N/A	BP1 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.	cspec
BP2	Not assessed	No phase data or alternative molecular explanation was identified that would support BP2 scoring.	cspec
BP3	N/A	BP3 is not applicable in this RASopathy MAP2K1 framework.	cspec
BP4	Not met	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.	cspec revel spliceai bayesdel
BP5	Not assessed	No alternative molecular diagnosis or clearly sufficient competing explanation for the phenotype was identified.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP7	N/A	BP7 is intended for synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply.	cspec spliceai

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