NM_006180.4:c.2033C>T

NTRK2 · NP_006171.2:p.(Ala678Val) · NM_006180.4

GRCh37: chr9:87570293 C>T · GRCh38: chr9:84955378 C>T

Gene: NTRK2 Transcript: NM_006180.4

Final call

VUS

PM2 supporting

Variant details

Gene

NTRK2

Transcript

NM_006180.4

Protein

NP_006171.2:p.(Ala678Val)

gnomAD AF

2.478394595117067e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	PVS1 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.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at the same amino acid residue (Ala678) has been reported as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo observation of NM_006180.4:c.2033C>T has been reported in the available evidence.	clinvar
PS3	Not met	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.	oncokb
PS4	Not met	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.	gnomad_v4
PS5	Not met	No reputable source has independently classified this variant as pathogenic. The single ClinVar submission from Labcorp Genetics classifies it as uncertain significance.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada clinvar
PM5	N/A	No same-residue comparator variant with a pathogenic classification was identified. Automated PM5 candidate harvesting did not identify eligible comparators at codon 678.	pm5_candidates
PM6	Not met	No confirmed de novo observation of NM_006180.4:c.2033C>T has been reported with maternity and paternity confirmed.	clinvar
PP1	Not met	No co-segregation data are available for NM_006180.4:c.2033C>T in affected families.
PP2	Not assessed	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.	pvs1_gene_context
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No evidence that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology attributable to NTRK2.
PP5	Not met	No reputable source has independently classified this variant as pathogenic. The sole ClinVar entry classifies it as uncertain significance.	clinvar
BA1	Not met	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).	gnomad_v4
BS1	Not met	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).	gnomad_v4
BS2	Not met	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.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrate no deleterious effect of p.Ala678Val on NTRK2 protein function or splicing.	oncokb spliceai
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease in affected families.
BP1	N/A	BP1 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.	pvs1_gene_context
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.	clinvar
BP6	Not met	No reputable source has classified this variant as benign or likely benign.	clinvar
BP7	N/A	BP7 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.

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