Variant classification summary

NM_004304.5:c.3522C>A

ALK · NP_004295.2:p.(Phe1174Leu) · NM_004304.5

GRCh37: chr2:29443695 G>T · GRCh38: chr2:29220829 G>T

Gene: ALK Transcript: NM_004304.5

Final call

Pathogenic

PS1 strong PS3 strong PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

ALK

Transcript

NM_004304.5

Protein

NP_004295.2:p.(Phe1174Leu)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong supports the exact recurrent activating ALK p.Phe1174Leu substitution.

2

Pathogenic: PS3 strong supports constitutive ALK signaling and cytokine-independent Ba/F3 transformation.

3

Pathogenic: PM1 moderate places F1174 in the ALK kinase-domain hotspot.

4

Pathogenic: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

5

Pathogenic: PP3 supporting reflects REVEL 0.752 above the generic threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS1 and PS3) satisfy the Pathogenic combination rule; PM1, PM2, and PP3 provide additional concordant support.

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	Met	Met: the exact ALK p.Phe1174Leu substitution is recurrently reported as activating and disease-associated in neuroblastoma functional studies.	PMID:18923525 PMID:18923523 clinvar
PS2	Not assessed	Not assessed: confirmed maternity, paternity, affected-proband status, and absence of family history are not documented.	PMID:18923523
PS3	Met	Met, strong: F1174L repeatedly caused constitutive ALK signaling and cytokine-independent Ba/F3 transformation across independent kinase and cellular assays.	PMID:18724359 PMID:18923523 PMID:18923525 PMID:20719933
PS4	Not assessed	Not assessed: tumor-cohort counts were reported, but no matched unaffected/control count is available to calculate the required OR >5.0 and 95% CI excluding 1.0.	PMID:18724359 PMID:18923525 PMID:20719933 PMID:20301782
PM1	Met	Met: ALK F1174 lies in the kinase domain and recurrent hotspot, with no queried-variant observations in gnomAD v2.1 or v4.1.	PMID:18923525 PMID:20719933 hotspots gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant was absent from gnomAD v2.1 and v4.1, satisfying the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no parental or offspring testing establishes a pathogenic variant in trans, and the inheritance mode is not documented as recessive.
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 qualifying pathogenic alternate missense change at ALK residue F1174 is documented in the available evidence.	pm5_candidates PMID:18923525 PMID:20719933
PM6	Not assessed	Not assessed: no evidence supports an assumed de novo event without confirmed parental testing.	PMID:18923523
PP1	Not assessed	Not assessed: no affected relatives or informative family meioses are documented for co-segregation.	PMID:18923523
PP2	Not assessed	Not assessed: gene-wide evidence for low benign missense variation and a common missense disease mechanism is not supplied.	gnomad_v2 gnomad_v4 PMID:18923525
PP3	Met	Met at supporting strength: missense REVEL 0.752 meets the generic PP3 threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: no individual patient phenotype or family history is available to determine whether it is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar shows one non-expert-laboratory Pathogenic submission with zero stars and no assertion criteria, not an expert-panel classification.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, rather than reaching the generic BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: no gnomAD v2.1 or v4.1 frequency was observed, so the filtering AF cannot reach the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier, homozygote, or hemizygote observation was documented for this variant.
BS3	Not assessed	Not assessed: no variant-specific functional study showed absence of damaging effect on ALK protein function or splicing.	PMID:18724359 PMID:18923523 PMID:18923525 PMID:20719933
BS4	Not assessed	Not assessed: no affected relatives with documented negative testing are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the evidence does not show that ALK disease is primarily caused by truncating variants rather than activating missense changes.	PMID:18923525 PMID:18923523
BP2	Not assessed	Not assessed: no affected-proband phase data show a pathogenic variant in trans or cis with this variant.
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 0.752 exceeds the generic BP4 supporting cutoff of <=0.29.	revel
BP5	Not met	Not met: no clinical case is documented with this exact variant and an independently established alternate molecular basis for disease.
BP6	Not met	Not met: ClinVar has no exact-variant Benign or Likely benign expert-panel classification; its sole submission is non-expert Pathogenic.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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