Variant classification summary

NM_004304.5:c.3824G>A

ALK · NP_004295.2:p.(Arg1275Gln) · NM_004304.5

GRCh37: chr2:29432664 C>T · GRCh38: chr2:29209798 C>T

Gene: ALK Transcript: NM_004304.5

Final call

Pathogenic

PS3 strong PM1 moderate PM2 supporting PP1 supporting PP3 moderate

Variant details

Gene

ALK

Transcript

NM_004304.5

Protein

NP_004295.2:p.(Arg1275Gln)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong reflects concordant biochemical, cellular, xenograft, and mouse-model evidence of constitutive ALK activation.

2

Pathogenic: PM1 moderate reflects the recurrent ALK kinase-domain R1275 hotspot observed in 54 of 1,596 neuroblastoma tumors.

3

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

4

Pathogenic: PP1 supporting reflects presence in both affected children in one family, with an asymptomatic maternal carrier limiting strength.

5

Pathogenic: PP3 moderate reflects REVEL 0.885 exceeding the generic moderate threshold of 0.773.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong plus 2 Moderate and 2 Supporting pathogenic criteria supports a 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: 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 reports ALK p.Arg1275Gln as c.3824G>A but does not establish the same amino-acid change from a different nucleotide change.	clinvar PMID:18923523 PMID:18923525
PS2	Not met	Not met: the variant was inherited from an asymptomatic mother by two affected children, rather than demonstrated de novo with confirmed maternity and paternity.	PMID:18923523
PS3	Met	Met, strong: independent biochemical, cellular, xenograft, and mouse-model assays showed constitutive ALK activation, including approximately 12-fold increased catalytic activity.	PMID:18923523 PMID:18923525 PMID:22072639 PMID:25517749 PMID:26554404
PS4	Not assessed	Not assessed: 54/1,596 affected tumors were reported, but no control count or matched-ancestry frequency permits the required OR/RR >5.0 and confidence interval excluding 1.0.	PMID:25517749 PMID:18923523 gnomad_v2 gnomad_v4
PM1	Met	Met: ALK R1275Q is a recurrent kinase-domain hotspot, observed in 54 of 1,596 neuroblastoma tumors (43% of ALK-mutated tumors).	PMID:22072639 PMID:25517749 hotspots
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 frequency threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: ALK-associated neuroblastoma predisposition is not established as recessive, and no pathogenic variant in trans is documented.	PMID:18923523
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 verified pathogenic ALK missense substitution at residue Arg1275 other than the observed p.Arg1275Gln is documented.	PMID:25517749 pm5_candidates
PM6	Not met	Not met: the variant was reported as maternally inherited in two affected children, not assumed de novo without parental confirmation.	PMID:18923523
PP1	Met	Met at supporting strength: ALK R1275Q was present in both affected children in one family, while an asymptomatic carrier mother limits stronger segregation use.	PMID:18923523
PP2	Not assessed	Not assessed: activating ALK missense disease mechanism is supported, but no gene-level measure establishes a low rate of benign missense variation.	PMID:22072639 PMID:25517749 gnomad_v2 gnomad_v4
PP3	Met	Met (moderate): REVEL 0.885 meets the generic PP3 moderate threshold of >=0.773 for this missense variant.	revel
PP4	Not assessed	Not assessed: ALK R1275Q is reported in neuroblastoma, but the current patient's phenotype and family history are not available to establish high specificity.	PMID:18923523 PMID:25517749
PP5	Not met	Not met: ClinVar has an exact-variant Pathogenic label, but expert-panel submissions are zero, so the PP5 eligibility condition is unmet.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency approaching the 5% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report no variant frequency, so the grpmax FAF cannot exceed the 1% BS1 default or a credible disease-specific threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: an asymptomatic heterozygous carrier was 39 years old, but full early-age penetrance required by BS2 is not established for ALK neuroblastoma.	PMID:18923523
BS3	Not met	Not met: no well-established negative functional result was identified; available exact-variant studies instead show constitutive ALK activation and oncogenic activity.	PMID:18923523 PMID:18923525 PMID:22072639 PMID:25517749 PMID:26554404
BS4	Not assessed	Not assessed: no affected non-carrier is documented; the only non-affected individual reported is a carrier mother.	PMID:18923523
BP1	Not met	Not met: ALK disease is characterized by recurrent activating missense variants, including R1275Q, rather than primarily truncating variants.	PMID:18923523 PMID:22072639 PMID:25517749
BP2	Not assessed	Not assessed: no cis or trans relationship between ALK p.Arg1275Gln and another pathogenic variant is documented.	PMID:18923523
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: REVEL 0.885 exceeds the generic BP4 supporting threshold of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no case-specific alternate molecular basis is documented to explain the disease independently of the ALK variant.
BP6	Not met	Not met: ClinVar has no exact-variant Benign or Likely benign expert-panel classification and records zero expert-panel submissions.	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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