Variant classification summary

NM_004304.5:c.3604G>A

ALK · NP_004295.2:p.(Gly1202Arg) · NM_004304.5

GRCh37: chr2:29443613 C>T · GRCh38: chr2:29220747 C>T

Gene: ALK Transcript: NM_004304.5

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 moderate BP5 supporting benign

Variant details

Gene

ALK

Transcript

NM_004304.5

Protein

NP_004295.2:p.(Gly1202Arg)

gnomAD AF

6.196416488416419e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong is supported by reproducible variant-specific drug-resistance and altered-signaling results.

2

Likely Pathogenic: PM2 supporting is supported by an extremely rare gnomAD allele frequency and zero homozygotes.

3

Likely Pathogenic: PP3 moderate is supported by REVEL 0.919.

4

BP5 supporting benign is applied, but it does not independently meet a benign rule or create conflicting evidence.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong pathogenic criterion plus 1 Moderate pathogenic criterion supports Likely Pathogenic; the single supporting benign BP5 criterion does not satisfy a benign rule.

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 met	Not met: p.Gly1202Arg is reported in resistant tumors, but no established pathogenic classification for the disease context is demonstrated.	PMID:22277784 clinvar
PS2	Not assessed	Not assessed: no documented affected proband with confirmed maternity and paternity is available to establish a de novo occurrence.
PS3	Met	Met, strong: three variant-specific studies showed reproducible drug resistance, including crizotinib IC50 382 nM versus 20 nM for the wild-type comparator.	PMID:22277784 PMID:26144315 PMID:26698910
PS4	Not assessed	Not assessed: one exact-variant observation occurred among 18 resistant patients, but no matched controls or OR/95% CI were reported for the required >5.0 enrichment test.	PMID:22277784
PM1	Not assessed	Not assessed: p.Gly1202Arg lies in the ALK kinase domain, but domain-wide absence of benign variation is not demonstrated.	PMID:24736079 PMID:22277784
PM2	Met	Met at supporting: gnomAD v4.1 AF is 6.19642e-07 with zero homozygotes, below the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no germline pathogenic partner, affected-proband observation, parental testing, or phase establishes the required in-trans configuration.	clinvar PMID:22277784 PMID:26698910
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 different missense change at ALK Gly1202 has been determined pathogenic in the supplied evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no affected proband or parental testing evidence supports an assumed de novo occurrence without confirmed maternity and paternity.
PP1	Not assessed	Not assessed: no affected relatives or informative meioses are documented for evaluating cosegregation of the variant with disease.
PP2	Not assessed	Not assessed: no qualifying ALK benign-missense rate and missense-mechanism evidence is supplied for PP2.
PP3	Met	Met at moderate strength: REVEL 0.919 exceeds the generic PP3 moderate threshold of >=0.773 but is below the strong threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history evidence is available showing a highly specific phenotype for a single-gene disease.	PMID:22277784
PP5	Not met	Not met: no expert-panel or equivalent reputable exact-variant pathogenic assertion is present; ClinVar is non-expert and conflicting with an overall uncertain-significance record.	clinvar oncokb
BA1	Not assessed	Not assessed: required gnomAD grpmax FAF is unavailable, although observed total AF is 6.19642e-07 versus the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not assessed	Not assessed: gnomAD grpmax FAF is unavailable; observed total AF is 6.19642e-07, below the generic 0.01 BS1 default.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: one gnomAD heterozygote is documented, but healthy-adult status, age, and full early penetrance are not established.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: variant-specific cellular and xenograft studies showed drug resistance and altered ALK signaling rather than no damaging effect on function or splicing.	PMID:22277784 PMID:26144315 PMID:26698910
BS4	Not assessed	Not assessed: no affected relatives lacking the variant are documented to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: ALK's relevant disease spectrum is not shown to be caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no germline cis or trans pathogenic partner is documented, and the available reports are somatic resistance studies without phase testing.	clinvar PMID:22277784 PMID:26698910
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 0.919 is above the generic BP4 supporting cutoff of <=0.29 for a missense variant.	revel
BP5	Met	Met: exact G1202R was a secondary mutation in ALK-rearranged NSCLC, providing an alternate molecular basis for the reported cancer.	PMID:22277784
BP6	Not met	Not met: no expert-panel or equivalent reputable exact-variant benign assertion is present in the available record.	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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