Variant classification summary

NM_002755.4:c.171G>T

MAP2K1 · NP_002746.1:p.(Lys57Asn) · NM_002755.4

GRCh37: chr15:66727455 G>T · GRCh38: chr15:66435117 G>T

Gene: MAP2K1 Transcript: NM_002755.4

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM1 moderate PM2 supporting

Variant details

Gene

MAP2K1

Transcript

NM_002755.4

Protein

NP_002746.1:p.(Lys57Asn)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS1 strong, based on the previously established pathogenic p.Lys57Asn change.

2

Pathogenic evidence: PS3 supporting, based on increased ERK signaling in an approved functional assay.

3

Pathogenic evidence: PM1 moderate, because residue 57 lies within the approved MAP2K1 critical domain at amino acids 43–61.

4

Pathogenic evidence: PM2 supporting, because the variant is absent from gnomAD v2.1 and v4.1.

Final determination: Under Rule11 of the ClinGen RASopathy Expert Panel MAP2K1 Version 2.3 framework, one strong pathogenic criterion plus one moderate pathogenic criterion supports a Likely Pathogenic classification.

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 explicitly marks PVS1 “Not Applicable,” and NM_002755.4:c.171G>T produces the missense change p.Lys57Asn.	cspec pvs1_variant_assessment
PS1	Met	Met, strong: the exact p.Lys57Asn change is previously established as pathogenic and reported repeatedly in MAP2K1 studies.	cspec clinvar PMID:18632602 PMID:25351745 PMID:29483135 PMID:26566875 PMID:29643386
PS2	Not assessed	Not assessed: no confirmed de novo observation or proband-parent genotype data are available to assign the VCEP's 1-, 2-, or 4-point PS2 thresholds.	cspec PMID:18632602 PMID:29643386
PS3	Met	Met at Supporting: the approved ERK activation assay shows increased ERK signaling for K57N, while the VCEP table pre-assigns this assay class PS3_Supporting.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies PMID:18632602 PMID:25351745 PMID:29483135 PMID:29643386
PS4	Not assessed	Not assessed: available counts concern somatic cancer or melorheostosis, not a VCEP-scored RASopathy cohort with the required PS4 point assignment.	cspec PMID:18632602 PMID:25351745 PMID:29643386
PM1	Met	Met, moderate: residue 57 lies within the VCEP-approved critical domain spanning amino acids 43-61.	cspec vcep_map2k_alignment
PM2	Met	Met, Supporting: the variant is absent from both default all-comers gnomAD v2.1 and v4.1, satisfying the VCEP's PM2 absence requirement.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the MAP2K1 VCEP specifies PM3 as not applicable for this autosomal-dominant RASopathy framework.	cspec
PM4	N/A	Not applicable: NM_002755.4:c.171G>T is a missense substitution, p.Lys57Asn, not a protein-length change covered by PM4.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: zero same-residue candidates were collected, but the comparator search ended with an HTTP 429 error and cannot exclude missing evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no unconfirmed de novo observation or parental genotype data are available to assign the VCEP's 0.5-, 1-, or 2-point PM6 thresholds.	cspec PMID:18632602 PMID:29643386
PP1	Not assessed	Not assessed: zero informative meioses or family segregation results are reported, below the VCEP thresholds of 3, 5, or 7 meioses.	cspec PMID:18632602 PMID:29643386
PP2	Not assessed	Not assessed: the VCEP requires a gnomAD missense z score >3.09, but no MAP2K1 missense z score is available.	gnomad_v4
PP3	Not met	Not met: REVEL 0.585 is below the VCEP's missense PP3 threshold of ≥0.7.	cspec revel spliceai
PP4	N/A	Not applicable: the MAP2K1 VCEP explicitly marks PP4 as not applicable and directs phenotype evidence to PS4.	cspec
PP5	N/A	Not applicable: the MAP2K1 VCEP explicitly prohibits use of PP5, regardless of available pathogenic reports.	cspec
BA1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, corresponding to an observed filtering allele frequency of 0%, below the 0.05% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report absence, corresponding to an observed filtering allele frequency of 0%, below the 0.025% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD absence provides no qualifying healthy individual, zygosity, phenotype, age, or VCEP BS2 point assignment.	cspec gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: the MAP2K1 VCEP explicitly marks BS3 Not applicable and assigns BS3_NA for the approved functional assay entries.	cspec vcep_svi_rasopathy_vcep_v2_approved_functional_studies
BS4	Not assessed	Not assessed: no informative meiosis or documented non-segregation in an unaffected relative is available for the VCEP's one-meiosis BS4 requirement.	cspec PMID:18632602 PMID:29643386
BP1	N/A	Not applicable: BP1 is limited to truncating or other LOF variants, whereas c.171G>T is a missense substitution.	cspec
BP2	Not assessed	Not assessed: no documented phase or affected-proband evidence establishes this variant in cis or trans with a pathogenic MAP2K1 variant.	cspec
BP3	N/A	Not applicable: the VCEP explicitly marks BP3 “Not Applicable,” and this variant is missense p.Lys57Asn rather than a repetitive-region protein-length change.	cspec pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.585 exceeds the VCEP's missense BP4 threshold of ≤0.3.	cspec revel
BP5	Not assessed	Not assessed: no patient-level alternate causative variant and phenotype evidence are available to evaluate the VCEP's BP5 point-based rule.	cspec
BP6	N/A	Not applicable: the MAP2K1 VCEP explicitly prohibits use of BP6 under its governing specification.	cspec
BP7	N/A	Not applicable: c.171G>T is a missense variant, outside BP7's synonymous, intronic, and non-coding scope.	cspec

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