About NTRK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK2 c.2033C>T, p.(Ala678Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_006180.4:c.2033C>T is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low allele frequency in gnomAD v4.1 (AF = 2.48e-06, 4/1,613,948 alleles, 0.00025%), well below the 0.1% threshold for PM2. This supports a pathogenic role under population-level rarity.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
4 / 1,613,948 alleles
gnomAD v4.1: 4 / 1,613,948 alleles. Recorded AF 2.47839e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52875759, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 20 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_006180.4:c.2033C>T (p.Ala678Val) in NTRK2 is a missense variant for which no CSPEC or VCEP gene-specific framework is available; classification proceeds under generic ACMG/AMP 2015 guidelines.
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low frequency in gnomAD v4.1 (4/1,613,948 alleles, AF = 2.48e-06, 0.00025%), meeting PM2 at supporting strength.
No pathogenic or benign criteria beyond PM2_supporting were met. PVS1/BP7 are not applicable to this missense variant. In silico predictors are discordant (REVEL 0.654 damaging, BayesDel 0.073 benign, SpliceAI delta 0.00), so PP3 and BP4 are not met. No functional studies, segregation data, de novo reports, or hotspot evidence were available.
The variant is reported in ClinVar (Variation ID 1393489) as Uncertain significance by a single clinical laboratory (Labcorp Genetics, SCV002166224), consistent with the limited evidence available for classification.
With only one supporting pathogenic criterion (PM2) met and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 1
PM2 SupportingNM_006180.4:c.2033C>T is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low allele frequency in gnomAD v4.1 (AF = 2.48e-06, 4/1,613,948 alleles, 0.00025%), well below the 0.1% threshold for PM2. This supports a pathogenic role under population-level rarity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 4/1
- 613
- 948 alleles (AF = 2.48e-6
- 0.00025%)
- no homozygotes.
- gnomAD-Canada: absent.
- ClinVar submitter Labcorp Genetics also applied PM2.
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at the same amino acid residue (Ala678) has been reported as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar shows only this variant (c.2033C>T
- p.Ala678Val) as the sole submission at this residue with a classification of uncertain significance.
- No pathogenic or likely pathogenic comparator exists at codon 678.
Sources
PS2 No de novo observation of NM_006180.4:c.2033C>T has been reported in the available evidence. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV002166224 from Labcorp Genetics does not report de novo origin.
- No publication identifies this variant as a confirmed de novo event.
Still missing
- De novo status could not be assessed without parental testing data.
Sources
PS3 No well-established functional studies demonstrate a damaging effect of p.Ala678Val on NTRK2 protein function. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence, and no publications with functional data for this exact variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific curated functional evidence.
- No publications in the evidence packet report functional data for this variant.
Still missing
- No experimental functional studies (in vitro or in vivo) available for p.Ala678Val.
Sources
PS4 The prevalence of NM_006180.4:c.2033C>T in affected individuals has not been shown to be significantly increased compared to controls. The variant is present at extremely low frequency in gnomAD (4/1,613,948 alleles) without an established case-control comparison. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 4 heterozygotes in 1
- 613
- 948 alleles (AF = 2.48e-6).
- No case-control or cohort study has established statistically significant enrichment in affected individuals.
Still missing
- No case-control or cohort study available for this variant.
Sources
PM1 Although p.Ala678Val resides within the tyrosine kinase domain of NTRK2 (amino acids ~544–821), cancer hotspot analysis did not identify this residue or surrounding region as a statistically significant mutational hotspot, and no functional domain-level constraint data are available to satisfy PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots analysis: residue A678 is not in a statistically significant hotspot.
- Variant lies in the kinase domain but lacks domain-specific benign variation constraint evidence.
Still missing
- No ClinGen-approved domain-level constraint or mutational hotspot data available for NTRK2 A678.
PM6 No confirmed de novo observation of NM_006180.4:c.2033C>T has been reported with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- ClinVar submission SCV002166224 does not report de novo status.
- No publication reports a confirmed de novo event for this variant.
Still missing
- De novo status cannot be assessed without parental testing.
Sources
PP1 No co-segregation data are available for NM_006180.4:c.2033C>T in affected families. Details ▾Hide ▴
Evidence considered
- No family-based segregation analysis has been reported for this variant.
Still missing
- No segregation data available.
PP3 In silico predictions are discordant: REVEL (0.654) predicts a damaging effect while BayesDel (0.073) predicts a benign effect, and SpliceAI (max delta = 0.00) shows no splice-altering potential. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.654 (above 0.5 threshold
- predicted damaging).
- BayesDel: 0.072725 (below typical pathogenic threshold
- predicted benign).
- SpliceAI: max delta = 0.00 (no predicted splice impact).
Sources
PP4 No evidence that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology attributable to NTRK2. Details ▾Hide ▴
Evidence considered
- No phenotype specificity data or clinical information about the proband is available.
Still missing
- Proband phenotype information not provided
- cannot evaluate phenotype specificity.
PP5 No reputable source has independently classified this variant as pathogenic. The sole ClinVar entry classifies it as uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter classification is Uncertain significance
- not pathogenic.
Sources
BA1 The variant allele frequency in gnomAD v4.1 (AF = 2.48e-6, 0.00025%) is well below the BA1 threshold of 1% (AF > 0.01). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 2.48e-6 (0.00025%)
- far below the BA1 1% threshold.
Sources
BS1 The variant allele frequency in gnomAD v4.1 (AF = 2.48e-6, 0.00025%) is well below the BS1 threshold of 0.3% (AF > 0.003). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 2.48e-6 (0.00025%)
- far below the BS1 0.3% threshold.
Sources
BS2 No evidence that this variant has been observed in a healthy adult individual, either in trans with a known pathogenic variant in a recessive disorder, or in homozygous state in a healthy adult for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: no homozygotes observed
- 4 heterozygous carriers of unknown phenotype.
Still missing
- No phenotype data available for gnomAD carriers.
Sources
BS3 No well-established functional studies demonstrate no deleterious effect of p.Ala678Val on NTRK2 protein function or splicing. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data.
- SpliceAI: max delta = 0.00
- no evidence of splicing impact.
Still missing
- No experimental functional studies available for this variant.
Sources
BS4 No segregation data are available to demonstrate lack of co-segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family-based segregation data available.
Still missing
- No segregation analysis available.
BP2 No evidence that this variant has been observed in trans with a known pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase information available for this variant relative to other NTRK2 variants.
Still missing
- No cis/trans phase data available.
BP4 Computational evidence is discordant: REVEL (0.654) predicts a damaging effect, while BayesDel (0.073) predicts a benign effect. Multiple lines of in silico evidence do not consistently suggest no impact on the gene or gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.654
- predicts damaging.
- BayesDel: 0.072725
- predicts benign.
- SpliceAI: max delta = 0.00
- no splice impact.
Sources
BP5 No evidence contradicting pathogenicity is available. The single ClinVar classification is uncertain significance, and the variant has been observed in COSMIC once in a somatic context, which does not support benign interpretation. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (not benign).
- COSMIC: COSV52875759
- observed once in somatic cancer context.
Sources
BP6 No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter classifies as Uncertain significance
- not benign.
Sources
PS5 No reputable source has independently classified this variant as pathogenic. The single ClinVar submission from Labcorp Genetics classifies it as uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: single submitter (Labcorp Genetics) classifies as Uncertain significance.
- No expert panel
- clinical laboratory
- or publication classifies this as pathogenic.
Sources
Not assessed · 1 · no assessment recorded
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While NTRK2 loss of function is supported as a germline disease mechanism, gene-level missense constraint metrics (e.g., gnomAD missense Z-score, o/e ratio, or HCI prior) are not available to determine whether the gene has a low rate of benign missense variation. HCI prior was not found for NTRK2. Details ▾Hide ▴
Evidence considered
- NTRK2 LoF mechanism is supported for germline disease.
- HCI prior scores are not available for NTRK2.
- No gnomAD missense constraint metrics were retrieved.
Still missing
- Missense constraint data (e.g.
- gnomAD Z-score
- o/e) needed to evaluate PP2 eligibility.
Sources
pvs1_gene_context
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_006180.4:c.2033C>T is a missense substitution (p.Ala678Val) and does not fall into the null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution p.(Ala678Val)
- not a predicted null variant.
- ClinGen SVI PVS1 decision tree (PMC6185798) confirms null-variant requirement.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo same-residue comparator variant with a pathogenic classification was identified. Automated PM5 candidate harvesting did not identify eligible comparators at codon 678. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection returned zero eligible comparators at residue Ala678.
Sources
pm5_candidates
BP1 N/ABP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. NTRK2 has literature evidence supporting both missense and truncating germline pathogenic variants, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- NTRK2 germline disease mechanism is not exclusively truncation-based
- missense variants are also implicated.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_006180.4:c.2033C>T is a missense variant (p.Ala678Val) with an amino acid change, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant produces a missense change p.(Ala678Val)
- not a synonymous substitution.
Identifiers
- Gene
- NTRK2
- Transcript
- NM_006180.4
- Coding (HGVS c.)
- NM_006180.4:c.2033C>T
- Protein (HGVS p.)
- NP_006171.2:p.(Ala678Val)
- GRCh38
- chr9:84955378 C>T
- GRCh37
- chr9:87570293 C>T
- ClinVar
- 1393489
- COSMIC
- COSV52875759
Gene diagram
Every interpreted variant in NTRK2, mapped onto the exon structure of NM_006180.4. Select a row to find it on the plot.
NTRK2NM_006180.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in NTRK2
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
4 / 1,613,948 alleles
AF 2.48e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,613,948 alleles · 0 hom · FAF 2.8e-07
| Ashkenazi Jewish1 / 29,602 | 3.4e-05 |
| East Asian1 / 44,888 | 2.2e-05 |
| European (non-Finnish)2 / 1,179,956 | 1.7e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613948 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.654
- BayesDel
- 0.073
How the predictions were used
PP3 In silico predictions are discordant: REVEL (0.654) predicts a damaging effect while BayesDel (0.073) predicts a benign effect, and SpliceAI (max delta = 0.00) shows no splice-altering potential. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.654 (above 0.5 threshold
- predicted damaging).
- BayesDel: 0.072725 (below typical pathogenic threshold
- predicted benign).
- SpliceAI: max delta = 0.00 (no predicted splice impact).
Sources
BP4 Computational evidence is discordant: REVEL (0.654) predicts a damaging effect, while BayesDel (0.073) predicts a benign effect. Multiple lines of in silico evidence do not consistently suggest no impact on the gene or gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.654
- predicts damaging.
- BayesDel: 0.072725
- predicts benign.
- SpliceAI: max delta = 0.00
- no splice impact.
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_006180.4:c.2033C>T is a missense variant (p.Ala678Val) with an amino acid change, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant produces a missense change p.(Ala678Val)
- not a synonymous substitution.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.654. BayesDel score = 0.072725.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,613,948 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1393489/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-87570293-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-84955378-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-84955378-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006180.4%3Ac.2033…
- OncoKB ↗www.oncokb.org/gene/NTRK2/A678V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121747441
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613948 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37815e-05; MAF= 0.00338%, 1/29602 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1393489)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.654. BayesDel score = 0.072725.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV52875759, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.