Variant classification summary

NM_002755.4:c.607G>A

MAP2K1 · NP_002746.1:p.(Glu203Lys) · NM_002755.4

GRCh37: chr15:66774131 G>A · GRCh38: chr15:66481793 G>A

Gene: MAP2K1 Transcript: NM_002755.4

Final call

VUS

PS3 supporting PM2 supporting PM5 moderate

Variant details

Gene

MAP2K1

Transcript

NM_002755.4

Protein

NP_002746.1:p.(Glu203Lys)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: functional studies showed increased ERK phosphorylation or MEK1 kinase activity.

2

PM2 supporting: the variant was absent from gnomAD v2.1 and v4.1 controls.

3

PM5 moderate: p.Glu203Gln was reported at the same codon in an individual with cardiofaciocutaneous syndrome.

Final determination: Under the MAP2K1 VCEP Version 2.3 rules, PS3 supporting, PM2 supporting, and PM5 moderate do not satisfy a pathogenic or benign rule, so the 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.607G>A is missense p.(Glu203Lys), not a listed null-variant class.	cspec pvs1_variant_assessment
PS1	Not met	Not met: the reviewed evidence identifies only the requested p.Glu203Lys change, not a distinct nucleotide change producing the same amino acid.	cspec PMID:22197931
PS2	Not assessed	Not assessed: ClinVar records a de novo origin, but no proband-level parental testing or de novo point assignment is documented.	cspec clinvar
PS3	Met	Met at Supporting: variant-specific studies showed increased ERK phosphorylation or kinase activity, while the VCEP table preassigns PS3_Supporting for MAP2K1 approved MEK and ERK assays.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:25351745 PMID:29483135 PMID:32641410 PMID:18456719 PMID:22197931
PS4	Not assessed	Not assessed: no qualifying germline RASopathy case-control counts or VCEP PS4 point assignment were available for this variant.	cspec PMID:18456719 PMID:22197931 PMID:23652378 PMID:24121147 PMID:32641410
PM1	Not met	Not met: residue 203 lies outside the VCEP-approved PM1 domains, AA 43-61 and AA 124-134.	cspec vcep_map2k_alignment
PM2	Met	Met at supporting: the variant was absent from gnomAD v2.1 and v4.1, satisfying the VCEP requirement that it be absent from gnomAD controls.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the MAP2K1 VCEP explicitly marks PM3 not applicable for this autosomal-dominant RASopathy framework.	cspec
PM4	N/A	Not applicable: PM4 requires an in-frame indel or stop-loss protein-length change, whereas c.607G>A produces missense p.(Glu203Lys).	cspec pvs1_variant_assessment
PM5	Met	Met at Moderate: PMID:22197931 reports the alternate missense change p.Glu203Gln at the same codon in an individual with cardiofaciocutaneous syndrome.	cspec PMID:22197931
PM6	Not assessed	Not assessed: a ClinVar de novo origin is recorded, but case-level parental testing and the required PM6 point assignment are unavailable.	cspec clinvar
PP1	Not assessed	Not assessed: no informative meioses or variant-positive affected relatives are documented.	cspec
PP2	Not assessed	Not assessed: the required MAP2K1 gnomAD missense z score is unavailable, so comparison with the >3.09 threshold cannot be made.	cspec gnomad_v2 gnomad_v4
PP3	Not met	Not met: REVEL score 0.621 is below the VCEP PP3 missense threshold of 0.7.	cspec revel
PP4	N/A	Not applicable: the MAP2K1 VCEP explicitly excludes PP4 and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the MAP2K1 VCEP states that PP5 is not for use.	cspec
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than reaching the BA1 threshold of at least 0.05%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than reaching the BS1 threshold of at least 0.025%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no qualifying healthy individual observation with zygosity, age, penetrance, and phenotype data was available for BS2 point scoring.	cspec
BS3	N/A	Not applicable: the VCEP marks BS3 not applicable for MAP2K1, and available functional studies report increased rather than normal MEK1 or ERK activity.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis or affected-relative non-segregation evidence is documented.	cspec
BP1	N/A	Not applicable: c.607G>A is a missense variant, whereas the VCEP BP1 rule is restricted to truncating variant classes.	cspec
BP2	Not assessed	Not assessed: no second pathogenic MAP2K1 variant with documented cis/trans phase and phenotype-compatible alternative cause is available.	cspec clinvar
BP3	N/A	Not applicable: the VCEP excludes BP3 because no known benign repetitive areas exist in RASopathy genes, and this variant is missense.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL score 0.621 exceeds the VCEP BP4 missense threshold of 0.3.	cspec revel
BP5	Not assessed	Not assessed: no alternative causative variant or VCEP BP5 point score was documented for this case.	cspec
BP6	N/A	Not applicable: the MAP2K1 VCEP states that BP6 is not for use.	cspec
BP7	N/A	Not applicable: c.607G>A is a missense variant, whereas BP7 covers synonymous, intronic, or non-coding variants.	cspec

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.