NM_006180.4:c.1979C>T

NTRK2 · NP_006171.2:p.(Pro660Leu) · NM_006180.4

GRCh37: chr9:87570239 C>T · GRCh38: chr9:84955324 C>T

Gene: NTRK2 Transcript: NM_006180.4

Final call

Likely Benign

BS1 supporting benign BS2 supporting benign BP4 supporting benign

Variant details

Gene

NTRK2

Transcript

NM_006180.4

Protein

NP_006171.2:p.(Pro660Leu)

gnomAD AF

0.0003707079839446807 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Missense substitution p.Pro660Leu is not a null variant (nonsense, frameshift, or canonical splice ±1,2); PVS1 null-variant framework does not apply.	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No alternative nucleotide change at c.1979 producing the same Pro660Leu amino acid change has been reported in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence data available for this variant in any curated database or publication.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or phenotype enrichment data available; variant is observed in population databases at appreciable frequency, inconsistent with enrichment in affected individuals.	gnomad_v2 gnomad_v4
PS5	Not met	ClinVar reports this variant as Likely benign (2 clinical laboratories) and Benign (1 clinical laboratory); no reputable source reports it as pathogenic.	clinvar
PM1	Not met	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.	gnomad_v2 gnomad_v4
PM2	Not met	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.	gnomad_v2 gnomad_v4
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo occurrence data available; no publications report de novo observation of this variant.
PP1	Not met	No co-segregation data available; variant has not been studied in affected families.
PP2	Not met	NTRK2 has not been established as having a low rate of benign missense variation; gnomAD data demonstrates significant missense variation tolerance at this gene.	gnomad_v2 gnomad_v4
PP3	Not met	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).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were provided for evaluation; cannot assess phenotypic specificity.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Met	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 gnomad_v4
BS2	Met	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.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant were identified.
BS4	Not met	No segregation data available to evaluate lack of co-segregation with disease in affected families.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No data available on observations of this variant in trans with a pathogenic variant for a fully penetrant recessive disorder.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No evidence of an alternate molecular basis for disease in individuals carrying this variant; no case-level data available.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; NM_006180.4:c.1979C>T is a missense variant (p.Pro660Leu).

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