Variant classification summary

NM_002755.4:c.370C>T

MAP2K1 · NP_002746.1:p.(Pro124Ser) · NM_002755.4

GRCh37: chr15:66729162 C>T · GRCh38: chr15:66436824 C>T

Gene: MAP2K1 Transcript: NM_002755.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

MAP2K1

Transcript

NM_002755.4

Protein

NP_002746.1:p.(Pro124Ser)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Supporting: approved functional assays show abnormal MEK/ERK pathway activation for p.Pro124Ser.

2

PM1 Moderate: p.Pro124Ser lies in the VCEP-defined critical domain at amino acids 124–134.

3

PM2 Supporting: the variant is absent from gnomAD v2.1 and v4.1.

4

PP3 Supporting: REVEL 0.855 exceeds the VCEP threshold of 0.7.

Final determination: Under the MAP2K1 VCEP Version 2.3 framework, one moderate criterion plus three supporting criteria satisfies neither a pathogenic nor a benign combination rule, so the final call is VUS.

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	Not applicable: the VCEP marks PVS1 not applicable, and c.370C>T is missense p.(Pro124Ser), not a defined null variant.	cspec
PS1	Not met	Not met: available reports describe the exact p.Pro124Ser variant, with no distinct nucleotide substitution producing the same amino-acid change established as pathogenic.	cspec PMID:22197931 PMID:32641410
PS2	Not assessed	Not assessed: no documented parental testing, de novo confirmation, or disease-specific point score is available.	cspec
PS3	Met	Met at Supporting: approved MAP2K1 functional assays and variant-specific ERK/MEK phosphorylation results support a damaging effect.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:22197931 PMID:29483135 PMID:32641410
PS4	Not assessed	Not assessed: no VCEP-qualified RASopathy case-control counts, control frequency, or PS4 point assignment are available for this variant.	cspec PMID:22197931 PMID:24265153 PMID:25370473 PMID:29483135 PMID:32641410
PM1	Met	Met, moderate: residue 124 falls within the VCEP-approved critical domain AA 124-134 specified for PM1.	cspec vcep_map2k_alignment
PM2	Met	Met at Supporting: NM_002755.4:c.370C>T is absent from both gnomAD v2.1 and v4.1, satisfying the VCEP requirement for absence from controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the MAP2K1 VCEP explicitly marks PM3 as not applicable.	cspec
PM4	Not met	Not met: c.370C>T is missense p.(Pro124Ser) with no protein length change, whereas PM4 requires an in-frame indel or stop-loss variant.	cspec
PM5	Not assessed	Not assessed: p.Pro124Gln is reported at codon 124, but its required likely-pathogenic status is not established in the available evidence.	cspec PMID:22197931 pm5_candidates
PM6	Not assessed	Not assessed: no RASopathy case documents assumed de novo status without confirmed maternity and paternity or provides a VCEP point score.	cspec
PP1	Not assessed	Not assessed: zero informative meioses are documented, so the VCEP thresholds of at least 3, 5, or 7 cannot be evaluated.	cspec
PP2	Not assessed	Not assessed: the VCEP requires a gnomAD missense z score >3.09, but no MAP2K1 missense z score is available.	cspec gnomad_v2 gnomad_v4
PP3	Met	Met: REVEL 0.855 meets the VCEP missense threshold of ≥0.7 for PP3 Supporting evidence.	cspec revel
PP4	N/A	Not applicable: the MAP2K1 VCEP explicitly marks PP4 as not applicable and directs phenotype evidence to PS4.	cspec
PP5	Met	Not applicable: the MAP2K1 VCEP prohibits PP5 use for this VCEP.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than meeting the VCEP BA1 threshold of ≥0.05% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than meeting the VCEP BS1 threshold of ≥0.025% filtering allele frequency.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports absence but provides no healthy homozygote or heterozygote observation from which the VCEP’s -4 or -1 point score can be assigned.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the MAP2K1 VCEP explicitly marks BS3 not applicable and pre-assigns BS3_NA for approved functional assays.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no affected-relative testing or non-segregation observation provides the one informative meiosis required by the VCEP.	cspec
BP1	N/A	Not applicable: BP1 is restricted to truncating variants, whereas this variant is the missense substitution p.Pro124Ser.	cspec
BP2	Not assessed	Not assessed: no documented germline phase or cis/trans pathogenic-variant observation is available to assign the VCEP's BP2 point threshold.	cspec
BP3	N/A	Not applicable: the VCEP marks BP3 not applicable and identifies no known benign repetitive areas in RASopathy genes.	cspec
BP4	Not met	Not met: REVEL 0.855 exceeds the VCEP missense BP4 threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or BP5 point value is documented for this case under the VCEP rule.	cspec
BP6	N/A	Not applicable: the MAP2K1 VCEP prohibits BP6 use for this VCEP.	cspec
BP7	N/A	Not applicable: c.370C>T is missense p.Pro124Ser, whereas BP7 is limited to synonymous, intronic, or non-coding variants.	cspec pvs1_variant_assessment

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.