Classification rationale

PM2 VUS

NTRK1 c.1031G>A

NM_002529.3:c.1031G>A (p.Gly344Glu) in NTRK1 is absent from all population databases (gnomAD v2.1, v4.1, Canada v1.0), meeting PM2 at supporting strength.¹ No additional pathogenic or benign criteria were met. The variant is absent from ClinVar, has no published functional data, and in silico predictors are discordant. COSMIC reports one somatic occurrence (COSV107439993).² Under generic ACMG/AMP 2015 rules, PM2_supporting alone is insufficient for classification. This variant is classified as a Variant of Uncertain Significance (VUS).³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗oncokb ↗revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_002529.3 · variants mapped to exon structure

NTRK1 NM_002529.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_002529.3:c.1031G>A is absent from all large population databases (gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0), with an allele frequency of 0.00, well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework.

Absent from gnomAD v2.1 (AF = 0.00).Absent from gnomAD v4.1 (AF = 0.00).Absent from gnomAD-Canada v1.0 (AF = 0.00).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No different nucleotide substitution at codon 344 resulting in the same amino acid change (p.Gly344Glu) has been reported as pathogenic.

PS2 No de novo observation has been reported for this variant; no parental or trio testing data are available in ClinVar, the literature, or any other evidence source.

PS3 No variant-specific functional studies were identified.

PS4 No case-control or prevalence data are available for this variant.

PM1 Position Gly344 is not in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 No different pathogenic missense change at codon 344 was identified.

PM6 No de novo observation has been reported for this variant.

PP1 No segregation data are available.

PP2 No HCI prior constraint data are available for NTRK1; the gene is not supported in the HCI prior database.

PP3 In silico predictors are discordant and do not provide multiple concordant lines of deleterious evidence.

PP4 No patient phenotype or clinical data are available for this case.

PP5 This variant is absent from ClinVar.

Benign

BA1 The variant is absent from gnomAD (AF = 0.00) and does not meet the >1% allele frequency threshold for BA1.

BS1 The variant is absent from gnomAD (AF = 0.00) and does not meet the >0.3% allele frequency threshold for BS1 in the generic ACMG/AMP framework.

BS2 No homozygous observations in healthy adults are reported.

BS3 No well-established functional studies demonstrating no deleterious effect exist for this variant.

BS4 No segregation or non-segregation data are available.

BP1 NTRK1-associated congenital insensitivity to pain with anhidrosis (CIPA) is caused by both missense and truncating loss-of-function variants.

BP2 No phase or trans/cis configuration data are available for this variant.

BP4 While BayesDel (0.160) and SpliceAI (max delta 0.00) are consistent with a benign interpretation, the REVEL score of 0.525 is borderline pathogenic.

BP5 No alternate molecular basis for disease has been identified in this case.

BP6 This variant is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.525. BayesDel score = 0.160315.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK1, a receptor tyrosine kinase, is altered by gene fusions in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107439993, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots