About NTRK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NTRK2 c.1979C>T, p.(Pro660Leu)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Supporting
BS1 · supporting
South Asian population allele frequency of 0.633% (gnomAD v4.1, 572/90420 alleles; gnomAD v2.1, 187/29718 alleles) exceeds the expected allele frequency for a fully penetrant NTRK2-related disorder, with 8 homozygous individuals observed in gnomAD v4.1.
BS2Supporting
BS2 · supporting
Observed in the homozygous state in 8 individuals in gnomAD v4.1 and 3 individuals in gnomAD v2.1; gnomAD excludes individuals with severe pediatric disease, which is inconsistent with a highly penetrant monogenic disorder caused by this variant.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign interpretation: REVEL score 0.313 (below 0.5 cutoff for deleterious), BayesDel score -0.27065 (negative/benign range), and SpliceAI max delta score 0.00 (no predicted splicing impact).
Recorded classification: Likely benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting benign, BS2 supporting benign, BP4 supporting benign; combination = 3 supporting benign, which maps to Likely Benign.
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
597 / 1,610,432 alleles
gnomAD v4.1: 597 / 1,610,432 alleles. Recorded AF 0.000370708. Recorded homozygote count 8.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000784145; MAF= 0.07841%, 190/242302 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00629248; MAF= 0.62925%, 187/29718 alleles, homozygotes = 3); grpmax FAF= 0.00555482.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0004886524052557281, 9/18418 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
2 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV52862623, n = 2 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: 3 met · 21 not met · 0 not assessed · 2 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.1979C>T (p.Pro660Leu) in NTRK2 is present in gnomAD at appreciable frequency with 8 homozygous individuals in v4.1 and a South Asian population allele frequency of 0.633%, exceeding the expected frequency for a fully penetrant NTRK2-related disorder.
Multiple lines of in silico evidence predict a benign effect: REVEL score 0.313, BayesDel score -0.27065, and SpliceAI max delta 0.00 indicating no splicing impact.
ClinVar reports this variant as Likely benign by 2 clinical laboratories and Benign by 1 clinical laboratory (Variation ID 2145557), though review status is 1-star.
No pathogenic missense variants at the same residue (p.Pro660) were identified, and no variant-specific functional studies or de novo reports exist for p.Pro660Leu.
No criteria match.
Met · 3
BS1 SupportingSouth Asian population allele frequency of 0.633% (gnomAD v4.1, 572/90420 alleles; gnomAD v2.1, 187/29718 alleles) exceeds the expected allele frequency for a fully penetrant NTRK2-related disorder, with 8 homozygous individuals observed in gnomAD v4.1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 SAS AF=0.629% (3 homozygotes)
- gnomAD v4.1 SAS AF=0.633% (8 homozygotes)
- grpmax FAF=0.590% (v4.1)
- exceeding 0.3% BS1 threshold.
Sources
BS2 SupportingObserved in the homozygous state in 8 individuals in gnomAD v4.1 and 3 individuals in gnomAD v2.1; gnomAD excludes individuals with severe pediatric disease, which is inconsistent with a highly penetrant monogenic disorder caused by this variant. Details ▾Hide ▴
Evidence considered
- 8 homozygotes in gnomAD v4.1 (all SAS)
- 3 homozygotes in gnomAD v2.1 (all SAS)
- homozygous state in presumed healthy population controls argues against full penetrance pathogenicity.
Sources
BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.313 (below 0.5 cutoff for deleterious), BayesDel score -0.27065 (negative/benign range), and SpliceAI max delta score 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL=0.313 (deleterious threshold ≥0.5 not met)
- BayesDel=-0.27065 (benign range)
- SpliceAI delta=0.00 (no splice alteration predicted).
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternative nucleotide change at c.1979 producing the same Pro660Leu amino acid change has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Only one nucleotide change (c.1979C>T) identified at this position.
Sources
PS2 No de novo occurrence data available for this variant in any curated database or publication. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar
- literature
- or database evidence.
Still missing
- No parental testing or de novo reports available for review.
PS3 No variant-specific functional studies identified for p.Pro660Leu; OncoKB reports unknown oncogenic effect; no literature with experimental functional data for this variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence
- no publications with functional assays of p.Pro660Leu identified.
Still missing
- No functional studies of p.Pro660Leu in any experimental system.
Sources
PS4 No case-control or phenotype enrichment data available; variant is observed in population databases at appreciable frequency, inconsistent with enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- No case-control data
- gnomAD frequencies do not support enrichment in disease cohorts.
Still missing
- No phenotype or case-control datasets available for review.
Sources
PM1 Although p.Pro660Leu lies within the protein kinase domain of NTRK2, the high population frequency (0.633% in South Asian population with 8 homozygotes in gnomAD v4.1) demonstrates this position tolerates missense variation; cancerhotspots.org does not identify this residue as a significant hotspot. Details ▾Hide ▴
Evidence considered
- Residue 660 is in the NTRK2 protein kinase domain but is not a statistically significant mutational hotspot
- high population frequency contradicts domain constraint for pathogenicity.
Sources
PM2 Variant is present in gnomAD v2.1 at overall AF=0.078% and South Asian AF=0.629% (187/29718 alleles, 3 homozygotes) and in gnomAD v4.1 at South Asian AF=0.633% (572/90420 alleles, 8 homozygotes); does not meet PM2 threshold for absent/rare in population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 190/242302 alleles (AF=0.078%)
- gnomAD v4.1: 597/1610432 alleles (AF=0.037%)
- SAS subpopulation AF=0.63% with multiple homozygotes.
Sources
PM5 No pathogenic missense variants at the same residue (p.Pro660) were identified in ClinVar; automatic PM5 candidate search returned no candidates and could not confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates
- no pathogenic comparator at p.Pro660 found in ClinVar.
Sources
pm5_candidates
PM6 No de novo occurrence data available; no publications report de novo observation of this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports for this variant in ClinVar
- literature
- or databases.
Still missing
- No de novo testing data available.
PP1 No co-segregation data available; variant has not been studied in affected families. Details ▾Hide ▴
Evidence considered
- No segregation analysis data available for this variant.
Still missing
- No family segregation data.
PP2 NTRK2 has not been established as having a low rate of benign missense variation; gnomAD data demonstrates significant missense variation tolerance at this gene. Details ▾Hide ▴
Evidence considered
- NTRK2 missense constraint metrics not established as meeting PP2 threshold
- gnomAD data shows substantial missense variation in the gene.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.313 (below 0.5 threshold), BayesDel score -0.27065 (benign range), SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
- REVEL=0.313
- BayesDel=-0.27065
- SpliceAI delta=0.00
- all in silico tools predict benign/no impact.
Sources
PP4 No patient phenotype or family history data were provided for evaluation; cannot assess phenotypic specificity. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- Patient phenotype data not provided.
PP5 ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory); no reputable source reports it as pathogenic. ClinVar review status is 1-star, which does not meet the 3-star expert panel threshold for PP5 application. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Likely benign/Benign (Variation ID 2145557)
- 3 submitting laboratories with 1-star aggregate review status.
Sources
BA1 Maximum observed population frequency is 0.633% in the South Asian population (gnomAD v4.1), which is below the BA1 threshold of >1% for any control population. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 SAS AF=0.633% (572/90420 alleles)
- v2.1 SAS AF=0.629% (187/29718 alleles)
- both below 1% BA1 threshold.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant were identified. Details ▾Hide ▴
Evidence considered
- No functional studies of p.Pro660Leu identified in the literature
- OncoKB reports unknown oncogenic effect.
Still missing
- No functional data for this variant to support or refute a benign effect.
BS4 No segregation data available to evaluate lack of co-segregation with disease in affected families. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No segregation analysis data.
BP1 Insufficient evidence that NTRK2-related disorders are exclusively caused by truncating variants; while loss-of-function is a supported disease mechanism, missense variants have also been implicated in NTRK2-related conditions and BP1 requires a gene where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- NTRK2 LoF is supported as a disease mechanism but the gene is not established as one where primarily truncating variants cause disease.
Sources
pvs1_gene_context
BP2 No data available on observations of this variant in trans with a pathogenic variant for a fully penetrant recessive disorder. Details ▾Hide ▴
Evidence considered
- No trans-phase observations available.
Still missing
- No data on co-occurrence with pathogenic variants.
BP5 No evidence of an alternate molecular basis for disease in individuals carrying this variant; no case-level data available. Details ▾Hide ▴
Evidence considered
- No cases reported with this variant and an alternative molecular diagnosis.
Still missing
- No case-level data available.
BP6 ClinVar review status is 1-star (criteria provided, single submitter), which does not meet the 2-star threshold typically required for BP6 application under generic ACMG/AMP. Although 3 clinical laboratories independently classify this variant as Likely benign or Benign, the aggregate review status does not meet BP6 evidentiary standards. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 2145557: Likely benign (2 labs)
- Benign (1 lab)
- aggregate review status is 1-star
- the sole cited PMID (28492532) is a general classification framework paper
- not variant-specific evidence.
Sources
PS5 ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory); no reputable source reports it as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification is Likely benign/Benign (Variation ID 2145557)
- not reported as pathogenic by any source.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution p.Pro660Leu is not a null variant (nonsense, frameshift, or canonical splice ±1,2); PVS1 null-variant framework does not apply. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a predicted null variant
- variant bucket is 'other' per PVS1 scaffold.
Sources
pvs1_variant_assessmentpvs1_gene_context
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_006180.4:c.1979C>T is a missense variant (p.Pro660Leu). Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Identifiers
- Gene
- NTRK2
- Transcript
- NM_006180.4
- Coding (HGVS c.)
- NM_006180.4:c.1979C>T
- Protein (HGVS p.)
- NP_006171.2:p.(Pro660Leu)
- GRCh38
- chr9:84955324 C>T
- GRCh37
- chr9:87570239 C>T
- ClinVar
- 2145557
- COSMIC
- COSV52862623
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NTRK2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
597 / 1,610,432 alleles
AF 0.000371 · 8 homozygotes · FAF 0.0059
gnomAD v2.1
190 / 242,302 alleles
AF 0.000784 · 3 homozygotes · FAF 0.00555
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00037 · 597 / 1,610,432 alleles · 8 hom · FAF 0.0059
| South Asian572 / 90,420 | 0.00638 hom |
| Middle Eastern3 / 6,056 | 0.0005 |
| Remaining individuals14 / 62,344 | 0.00022 |
| African/African American1 / 74,950 | 1.3e-05 |
| European (non-Finnish)7 / 1,178,378 | 5.9e-06 |
0 alternate alleles recorded in 5 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00078 · 190 / 242,302 alleles · 3 hom · FAF 0.0056
| South Asian187 / 29,718 | 0.00633 hom |
| Remaining individuals2 / 5,940 | 0.00034 |
| European (non-Finnish)1 / 109,152 | 9.2e-06 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000370708; MAF= 0.03707%, 597/1610432 alleles, homozygotes = 8) and has highest observed frequency in the South Asian population (AF= 0.00632603; MAF= 0.63260%, 572/90420 alleles, homozygotes = 8); grpmax FAF= 0.00589716.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000784145; MAF= 0.07841%, 190/242302 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00629248; MAF= 0.62925%, 187/29718 alleles, homozygotes = 3); grpmax FAF= 0.00555482.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0004886524052557281, 9/18418 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.313
- BayesDel
- -0.271
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign interpretation: REVEL score 0.313 (below 0.5 cutoff for deleterious), BayesDel score -0.27065 (negative/benign range), and SpliceAI max delta score 0.00 (no predicted splicing impact). Details ▾Hide ▴
Evidence considered
- REVEL=0.313 (deleterious threshold ≥0.5 not met)
- BayesDel=-0.27065 (benign range)
- SpliceAI delta=0.00 (no splice alteration predicted).
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.313 (below 0.5 threshold), BayesDel score -0.27065 (benign range), SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
- REVEL=0.313
- BayesDel=-0.27065
- SpliceAI delta=0.00
- all in silico tools predict benign/no impact.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; NM_006180.4:c.1979C>T is a missense variant (p.Pro660Leu). Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous
- BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.313. BayesDel score = -0.27065.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a methods paper describing a variant classification framework; it does not discuss the NTRK2 p.Pro660Leu variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
597 / 1,610,432 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
2 Likely benign · 1 Benign
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/2145557/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-87570239-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-84955324-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-84955324-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_006180.4%3Ac.1979…
- OncoKB ↗www.oncokb.org/gene/NTRK2/P660L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121755005
- 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= 0.000370708; MAF= 0.03707%, 597/1610432 alleles, homozygotes = 8) and has highest observed frequency in the South Asian population (AF= 0.00632603; MAF= 0.63260%, 572/90420 alleles, homozygotes = 8); grpmax FAF= 0.00589716.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000784145; MAF= 0.07841%, 190/242302 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00629248; MAF= 0.62925%, 187/29718 alleles, homozygotes = 3); grpmax FAF= 0.00555482.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0004886524052557281, 9/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 2145557)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.313. BayesDel score = -0.27065.
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; COSV52862623, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.