Variant classification summary

NM_002529.4:c.1783G>A

NTRK1 · NP_002520.2:p.(Gly595Arg) · NM_002529.4

GRCh37: chr1:156846342 G>A · GRCh38: chr1:156876550 G>A

Gene: NTRK1 Transcript: NM_002529.4

Final call

VUS

PS3 supporting PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

NTRK1

Transcript

NM_002529.4

Protein

NP_002520.2:p.(Gly595Arg)

gnomAD AF

4.960286704571524e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: variant-specific studies showed altered TRKA function and marked inhibitor resistance.

2

PM1 moderate: p.Gly595Arg is in the critical NTRK1 kinase-domain solvent front and is extremely rare in gnomAD.

3

PM2 supporting: gnomAD v4.1 filtering grpmax FAF is 5.53e-06.

4

PP3 supporting: REVEL 0.926 exceeds the generic missense threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, 1 moderate plus 3 supporting criteria satisfies no pathogenic, likely pathogenic, benign, or likely benign combination, so the call is 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 p.Gly595Arg but no independently established pathogenic variant with the same amino-acid change from a different nucleotide change.
PS2	Not assessed	Not assessed: parental genotypes, maternity/paternity confirmation, affected-proband phenotype, and family-history status are not documented.
PS3	Met	Met at supporting: variant-specific biochemical, cellular, and tumor-model studies showed altered TRKA function, including entrectinib IC50 greater than 1000 nM in engineered Ba/F3 cells.	PMID:26546295 PMID:28578312 PMID:29466156 oncokb
PS4	Not met	Not met: no affected-versus-control counts, odds ratio, or confidence interval establish the required OR >5.0 with a confidence interval excluding 1.0.	PMID:24121147 PMID:29419974 PMID:26546295
PM1	Met	Met: p.Gly595Arg is a solvent-front kinase-domain variant, with gnomAD v4.1 AF 4.96e-6 and zero homozygotes, supporting a critical functional-domain location without common benign variation.	PMID:29466156 PMID:28578312 gnomad_v4 hotspots
PM2	Met	Met at supporting: gnomAD v4.1 filtering grpmax FAF is 5.53e-06, below the PM2 threshold of 0.0001, with 8 alleles and no homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected-proband observation or parental/offspring phase result shows c.1783G>A in trans with a pathogenic NTRK1 variant.	clinvar
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 Gly595 is documented as an established pathogenic variant in the available evidence.	pm5_candidates
PM6	Not assessed	Not assessed: no parental testing or documented assumed-de-novo observation is available for the variant.
PP1	Not assessed	Not assessed: zero informative affected-relative co-segregations or meioses are documented for the variant.
PP2	Not assessed	Not assessed: NTRK1 loss of function is supported, but no validated gene-wide evidence establishes both low benign missense variation and common missense disease causation.
PP3	Met	Met at supporting: REVEL 0.926 exceeds the generic missense PP3 supporting threshold of >=0.644.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not supplied, so specificity for a single-gene disease cannot be evaluated.
PP5	Not met	Not met: ClinVar reports the exact variant as uncertain significance with zero expert-panel submissions, and no reviewed source reports it as pathogenic.	clinvar PMID:26546295 PMID:28578312 PMID:29466156
BA1	Not met	Not met: filtering grpmax FAF is 5.53e-06 in gnomAD v4.1 and 1.913e-05 in v2.1, both below the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: filtering grpmax FAF is at most 1.913e-05, far below the 0.01 generic BS1 threshold for an elevated disease frequency.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: no healthy adult homozygote is observed, with 0 homozygotes reported in gnomAD v4.1 across 1,612,810 alleles.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: variant-specific studies showed altered TRKA function, including increased ATP affinity (Km 6 µM versus 51 µM) and marked inhibitor resistance, not a normal functional result.	PMID:26546295 PMID:28578312 PMID:29466156 oncokb
BS4	Not assessed	Not assessed: no informative affected relatives lacking the variant are documented, so non-segregation cannot be evaluated.
BP1	Not assessed	Not assessed: NTRK1 loss of function is supported, but the evidence does not show that known disease-causing variants are primarily truncating.
BP2	Not assessed	Not assessed: no documented cis or trans observation with a pathogenic variant is available for c.1783G>A.	clinvar
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 0.926 is above the generic missense BP4 supporting cutoff of <=0.29.	revel
BP5	Not assessed	Not assessed: cancer resistance reports are unrelated to this patient's hereditary disease, and no patient-specific alternate molecular basis is documented.	PMID:26546295 PMID:28578312
BP6	Not met	Not met: the exact variant is uncertain significance in ClinVar with no expert-panel submission, and no reviewed source reports benignity.	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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