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.1 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.2 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.3 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.4
NTRK2
Final classification
Likely Benign
NTRK2 c.1979C>T · p.Pro660Leu
NTRK2
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.
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.
Classification rationale
BS1BS2BP4
Likely Benign
NTRK2 c.1979C>T
BS1 + BS2 + BP4
→
Likely Benign
Gene diagram
· NM_006180.4 · variants mapped to exon structure
NTRK2
NM_006180.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
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.
gnomAD v2.1 SAS AF=0.629% (3 homozygotes)gnomAD v4.1 SAS AF=0.633% (8 homozygotes)grpmax FAF=0.590% (v4.1)
✓
BS2
supporting
Benign
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.
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.
✓
BP4
supporting
Benign
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).
REVEL=0.313 (deleterious threshold ≥0.5 not met)BayesDel=-0.27065 (benign range)SpliceAI delta=0.00 (no splice alteration predicted).
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at c.1979 producing the same Pro660Leu amino acid change has been reported in ClinVar or the literature.
PS2
No de novo occurrence data available for this variant in any curated database or publication.
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.
PS4
No case-control or phenotype enrichment data available; variant is observed in population databases at appreciable frequency, inconsistent with enrichment in affected individuals.
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.
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.
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.
PM6
No de novo occurrence data available; no publications report de novo observation of this variant.
PP1
No co-segregation data available; variant has not been studied in affected families.
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.
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).
PP4
No patient phenotype or family history data were provided for evaluation; cannot assess phenotypic specificity.
PP5
ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory); no reputable source reports it as pathogenic.
Benign
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.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant were identified.
BS4
No segregation data available to evaluate lack of co-segregation with disease in affected families.
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.
BP2
No data available on observations of this variant in trans with a pathogenic variant for a fully penetrant recessive disorder.
BP5
No evidence of an alternate molecular basis for disease in individuals carrying this variant; 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.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0004886524052557281, 9/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.037%
· 597 / 1,610,432
8 hom · FAF 0.59%
8 hom · FAF 0.59%
South Asian 572 / 90,420 |
0.63% 8 hom |
Middle Eastern 3 / 6,056 |
0.05% |
Remaining individuals 14 / 62,344 |
0.022% |
African/African American 1 / 74,950 |
0.0013% |
European (non-Finnish) 7 / 1,178,378 |
0.00059% |
+ 5 not observed (Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.078%
· 190 / 242,302
3 hom · FAF 0.56%
3 hom · FAF 0.56%
South Asian 187 / 29,718 |
0.63% 3 hom |
Remaining individuals 2 / 5,940 |
0.034% |
European (non-Finnish) 1 / 109,152 |
0.00092% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.049%
· 9 / 18,418
0 hom · FAF 0.34%
0 hom · FAF 0.34%
South Asian 9 / 1,362 |
0.66% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)
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
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. NTRK2, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers.
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; COSV52862623, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR