Variant classification summary

NM_004304.5:c.3586C>A

ALK · NP_004295.2:p.(Leu1196Met) · NM_004304.5

GRCh37: chr2:29443631 G>T · GRCh38: chr2:29220765 G>T

Gene: ALK Transcript: NM_004304.5

Final call

VUS

PS3 strong PM2 supporting

Variant details

Gene

ALK

Transcript

NM_004304.5

Protein

NP_004295.2:p.(Leu1196Met)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 strong: independent cellular, biochemical, and mouse-xenograft assays showed ALK L1196M kinase activation and marked crizotinib resistance.

2

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1, consistent with the applicable low-frequency threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, PS3 at strong strength plus PM2 at supporting strength satisfies no pathogenic, likely pathogenic, benign, or likely benign combination rule, resulting in 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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the evidence documents only ALK p.Leu1196Met itself, with no established pathogenic alternate nucleotide change producing the same amino-acid substitution.	clinvar PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784
PS2	Not assessed	Not assessed: no proband disease documentation, family-history assessment, or confirmed maternity and paternity results are available.
PS3	Met	Met (strong): independent cellular, biochemical, and mouse-xenograft assays showed ALK L1196M kinase activation and marked crizotinib resistance, including IC50 >1000 nM and complete xenograft insensitivity.	PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784
PS4	Not met	Not met: affected-patient observations lacked unaffected/control counts, so no OR could be computed against the required OR >5.0 threshold with a CI excluding 1.0.	PMID:22235099 PMID:22277784
PM1	Not assessed	Not assessed: L1196 is in the ALK kinase gatekeeper pocket, but no evidence establishes absence of benign variation across the entire critical domain.	PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, consistent with the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, pathogenic-in-trans, or parental/offspring phase data establish the required recessive allelic observation.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no distinct pathogenic missense substitution at ALK residue 1196 was identified apart from the queried p.Leu1196Met.	pm5_candidates clinvar PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784
PM6	Not assessed	Not assessed: no proband disease documentation or parental testing results support an assumed de novo occurrence.
PP1	Not assessed	Not assessed: no affected family members with genotype and phenotype data are available to evaluate co-segregation.
PP2	Not assessed	Not assessed: no gene-wide evidence establishes both low benign missense variation and a common missense disease mechanism for ALK.
PP3	Not met	Not met: missense REVEL score 0.598 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the available record lacks the present patient’s phenotype or family history needed to determine whether it is highly specific for a single-gene disease.	PMID:22235099 PMID:22277784
PP5	Not met	Not met: ClinVar shows one exact-variant Likely pathogenic laboratory submission, but no expert-panel classification required for PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF reaching the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF exceeding the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult carrier observation or validated early-onset, fully penetrant germline ALK disorder model is available.
BS3	Not assessed	Not assessed: no well-established assay demonstrated that ALK L1196M has no damaging effect on protein function or splicing.	PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784
BS4	Not assessed	Not assessed: no affected relatives and corresponding genotype data are available to evaluate lack of segregation.
BP1	Not assessed	Not assessed: available ALK evidence focuses on somatic activating missense variants and does not establish a primarily truncating disease spectrum.	PMID:21613408 PMID:22034911 PMID:22235099 PMID:22277784
BP2	Not assessed	Not assessed: no affected-individual evidence establishes this variant in trans or cis with a pathogenic variant under the BP2 rule.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.598 exceeds the generic BP4 supporting threshold of 0.29.	revel
BP5	Not met	Not met: no case-specific alternate molecular basis explaining the disease instead of ALK c.3586C>A is documented.
BP6	Not met	Not met: ClinVar has no exact-variant Benign or Likely benign expert-panel classification; its sole submission is laboratory Likely pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.