Variant classification summary

NM_004304.4:c.4148T>C

ALK · NP_004295.2:p.(Ile1383Thr) · NM_004304.4

GRCh37: chr2:29419652 A>G · GRCh38: chr2:29196786 A>G

Gene: ALK Transcript: NM_004304.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ALK

Transcript

NM_004304.4

Protein

NP_004295.2:p.(Ile1383Thr)

gnomAD AF

6.816117266960049e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004304.4:c.4148T>C (p.Ile1383Thr) is a missense variant in exon 28 of the ALK gene. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes).

2

In silico analysis with REVEL predicts a damaging effect (score=0.861), though additional predictors are equivocal (BayesDel score=0.373; SpliceAI max delta=0.0). Ambry Genetics cited in silico evidence (PP3) in their ClinVar submission.

3

ClinVar Variation ID 575890: classified as Uncertain Significance by 2 clinical laboratories (review status: criteria provided, single submitter). No expert panel classification exists.

4

No variant-specific functional data, cosegregation data, case-control data, or de novo reports were identified in the literature. OncoKB classifies this variant as Unknown Oncogenic Effect.

5

This variant is not a null variant (PVS1 not applicable) and does not fall in a statistically significant mutational hotspot (PM1 not met). No same-residue pathogenic comparators were identified (PM5 not applicable).

6

No benign criteria are met: the variant is too rare for BA1/BS1, not observed in homozygous state (BS2 not met), and no benign functional evidence exists (BS3 not met). In silico predictors are mixed and do not support multiple lines of benign evidence (BP4 not met). BP1 is not applicable as ALK missense variants are established disease-causing mechanisms.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense substitution (p.Ile1383Thr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) applies only to predicted null variants; the variant does not fall into any PVS1 bucket.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No alternate nucleotide change at codon 1383 producing the same amino acid change (Ile1383Thr) has been reported as pathogenic. PS1 requires a different nucleotide substitution resulting in the same missense change that is established as pathogenic.
PS2	N/A	No de novo occurrence data with confirmed paternity and maternity are available for this variant.
PS3	Not met	No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional data. No publications with experimental functional characterization of p.Ile1383Thr were found.	oncokb
PS4	Not met	No variant-specific case-control or prevalence data in affected individuals are available. The variant has been observed in ClinVar as VUS by 2 clinical laboratories, but no enriched prevalence in cases versus controls has been demonstrated.	clinvar
PS5	N/A	No evidence that this variant has been found in trans with a pathogenic variant in the same gene.
PM1	Not met	This variant (p.Ile1383Thr) lies within the ALK kinase domain (residues ~1116-1392), a functionally important region. However, the residue is not a statistically significant hotspot per cancerhotspots.org, and no variant-specific domain-level evidence from the literature links this position to germline pathogenicity. Domain membership alone, without a specific mutational hotspot or functional domain characterization showing enrichment of pathogenic variants at or near this residue, is insufficient for PM1 under generic ACMG.	oncokb
PM2	Met	This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes; grpmax FAF=4.29e-6). The allele frequency is well below the 0.1% threshold for PM2 under generic ACMG.	gnomad_v2 gnomad_v4
PM5	N/A	No pathogenic missense variant at the same codon (Ile1383) was identified as a PM5 comparator. Automated candidate harvesting found no same-residue candidates.	pm5_candidates
PM6	N/A	No de novo occurrence data (without confirmed paternity/maternity) are available for this variant.
PP1	Not met	No cosegregation data with disease in families are available for this variant.
PP2	Not met	No gene-level missense constraint data (e.g., gnomAD missense Z-score) were available in the evidence packet to assess whether ALK has a low rate of benign missense variation. Without explicit constraint metrics, PP2 cannot be applied.
PP3	Met	REVEL predicts a damaging effect (score=0.861, above the 0.75 threshold). BayesDel is borderline (score=0.373, below 0.5) and SpliceAI predicts no splice impact (max delta=0.0). While in silico predictors are mixed, the strong REVEL score supports a deleterious prediction and is consistent with one ClinVar submitter (Ambry Genetics) citing in silico evidence for this variant. Applied at supporting strength due to lack of full multi-tool concordance.	revel bayesdel spliceai clinvar
PP4	Not met	No patient-specific phenotype or family history data are available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classifies this variant as Uncertain Significance (2 clinical laboratories, review status: criteria provided, single submitter). The classification is not pathogenic/likely pathogenic and the review status is not expert panel (3-star). PP5 requires a reputable source to have classified the variant as pathogenic. The cited ClinVar publications (PMID:20301782, GeneReviews; PMID:25394175, ACMG guideline) are gene-level references that do not mention this variant.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 6.82e-6 (0.00068%), far below the 1% BA1 threshold. BA1 is not met.	gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 6.82e-6 (0.00068%), far below the 0.3% BS1 threshold. BS1 is not met.	gnomad_v4
BS2	Not met	No homozygous individuals are observed in gnomAD v4.1 (0 homozygotes out of 1,613,822 alleles). BS2 requires observation in a healthy adult homozygous state for a fully penetrant disorder.	gnomad_v4
BS3	Not met	No well-established functional studies show no damaging effect for this variant. No experimental functional data of any kind were identified for p.Ile1383Thr.	oncokb
BS4	Not met	No non-segregation data with disease in families are available for this variant.
BP1	N/A	ALK missense variants are established causes of neuroblastoma predisposition (e.g., F1174L, R1275Q). The disease mechanism is not limited to truncating variants; both missense and truncating germline variants are associated with disease. BP1 applies only when a gene's disease mechanism is primarily through truncating variants.	pvs1_gene_context
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic variant in a fully penetrant dominant disorder.
BP4	Not met	REVEL predicts a damaging effect (score=0.861). While SpliceAI is neutral (max delta=0.0) and BayesDel is borderline (0.373), the strong REVEL pathogenic prediction precludes BP4, which requires multiple lines of computational evidence suggesting no impact on gene product. The in silico evidence is mixed and does not support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been found in a case with an alternate molecular basis for disease.
BP6	Not met	ClinVar classifies this variant as Uncertain Significance, not benign/likely benign. The review status is 'criteria provided, single submitter' (1-star), not expert panel. No reputable source reports this variant as benign.	clinvar
BP7	N/A	This is a missense variant (p.Ile1383Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	This is a missense substitution, not an in-frame indel in a non-repeat region. BP3 applies to in-frame deletions/insertions.
PM3	N/A	No evidence that this variant has been found in trans with a pathogenic variant for a recessive disorder.
PM4	N/A	This is a missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss).

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.