Variant classification summary

NM_001127208.2:c.5651C>A

TET2 · NP_001120680.1:p.(Thr1884Asn) · NM_001127208.2

GRCh37: chr4:106197318 C>A · GRCh38: chr4:105276161 C>A

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Thr1884Asn)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_001127208.2:c.5651C>A (p.Thr1884Asn) is a missense variant in TET2, a gene with emerging germline disease association involving autoimmune lymphoproliferative syndrome-like phenotypes and hematologic malignancy.

2

The variant is absent from gnomAD v2.1 and v4.1 (0/1,551,598 alleles) and gnomAD-Canada, meeting PM2 at moderate strength.

3

Multiple in silico tools predict a neutral or benign effect: BayesDel score is -0.27313 (benign), REVEL score is 0.302 (neutral), and SpliceAI delta is 0.00 (no splice impact), meeting BP4 at supporting benign strength.

4

The variant is absent from ClinVar and has not been classified by any expert panel. OncoKB reports an 'Unknown Oncogenic Effect' with no variant-specific functional evidence.

5

One somatic observation exists in COSMIC (COSV54403709, n=1), but this does not independently support germline pathogenicity.

6

No functional studies, family segregation data, de novo observations, or case-control data are available. Literature search returned zero variant-specific PMIDs.

7

With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), this variant does not meet the threshold for Likely Pathogenic (requires ≥2 moderate or ≥1 moderate + ≥4 supporting) or Likely Benign (requires ≥1 strong benign + ≥1 supporting benign, or ≥2 supporting benign). The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.

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	NM_001127208.2:c.5651C>A is a missense variant (p.Thr1884Asn) and does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision tree (PMC6185798) is not applicable to missense substitutions.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No pathogenic variant with the same amino acid change (p.Thr1884Asn) has been established in ClinVar or the literature. The variant is absent from ClinVar entirely.	clinvar
PS2	N/A	No de novo testing data (with confirmed paternity and maternity) are available for this variant.
PS3	Not assessed	No well-established functional studies are available for NM_001127208.2:c.5651C>A. Literature search returned zero PMIDs, and OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data are available to assess whether this variant is statistically enriched in affected individuals.
PS5	Not assessed	No reputable source has classified this missense variant as pathogenic, and no same-residue pathogenic comparator variants were identified to support PS5 application.	clinvar pm5_candidates
PM1	Not met	This variant does not reside in a statistically significant mutational hotspot as determined by Cancer Hotspots analysis.
PM2	Met	NM_001127208.2:c.5651C>A is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (0/1,551,598 alleles; AF=0%), and gnomAD-Canada v1.0, meeting the PM2 threshold of <0.1% under the generic ACMG/AMP framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic missense variant has been identified at amino acid residue Thr1884 to serve as a PM5 comparator. The automated PM5 candidate search found zero same-residue candidates.	pm5_candidates
PM6	Not assessed	No de novo observation data are available for this variant. The variant is absent from ClinVar and no publications report a de novo occurrence.
PP1	Not assessed	No family segregation data are available for this variant.
PP2	Not assessed	Insufficient data are available to determine whether TET2 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. TET2 germline disease context is recognized, but gene-level missense constraint metrics (e.g., Z-score) are not available for this assessment.
PP3	Not met	Multiple in silico tools do not support a deleterious effect. REVEL score is 0.302 (below the typical pathogenicity threshold of 0.5), BayesDel score is -0.27313 (predicting benign), and SpliceAI predicts no splice impact (max delta = 0.00).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to determine whether the clinical presentation is highly specific for a TET2-related disorder.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar, and OncoKB reports an 'Unknown Oncogenic Effect.'	clinvar oncokb
BA1	Not met	The variant is absent from gnomAD v4.1 (0/1,551,598 alleles; AF=0%), well below the BA1 threshold of >1%.	gnomad_v4
BS1	Not met	The variant is absent from gnomAD v4.1 (0/1,551,598 alleles; AF=0%), well below the BS1 threshold of >0.3%.	gnomad_v4
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults where full penetrance would be expected at an early age.
BS3	Not assessed	No well-established functional studies are available to demonstrate a lack of damaging effect for this variant.
BS4	Not assessed	No family segregation data are available to assess lack of segregation with disease.
BP1	Not assessed	Insufficient evidence to determine whether TET2-associated germline disease is primarily caused by truncating variants. While TET2 loss-of-function is a supported disease mechanism, the relative contribution of missense versus truncating variants has not been established.
BP2	Not assessed	No phase data (cis or trans) are available for this variant with respect to any other variant in TET2.
BP4	Met	Multiple lines of computational evidence predict no damaging effect. BayesDel score is -0.27313 (benign prediction), REVEL score is 0.302 (neutral, below pathogenicity threshold), and SpliceAI predicts no splice impact (max delta = 0.00).	revel bayesdel spliceai
BP5	Not assessed	No data are available indicating that this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies only to synonymous variants. NM_001127208.2:c.5651C>A is a missense substitution (p.Thr1884Asn).
BP3	N/A	BP3 applies only to in-frame deletions/insertions in a repetitive region. This is a missense substitution.
PM3	N/A	PM3 requires detection in trans with a known pathogenic variant. No phase data or trans observations are available.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a missense substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.