NM_001127208.2:c.5666C>T

TET2 · NP_001120680.1:p.(Pro1889Leu) · NM_001127208.2

GRCh37: chr4:106197333 C>T · GRCh38: chr4:105276176 C>T

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Pro1889Leu)

gnomAD AF

6.445284050113373e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.5666C>T (p.Pro1889Leu) is a missense variant in exon 11 of TET2.

This variant is extremely rare in population databases: absent from gnomAD v2.1 (0/155,736 alleles) and present at an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1 (1/1,551,522 alleles), well below the 0.1% threshold for PM2 (supporting).

Multiple in silico predictors suggest the variant is benign: REVEL score 0.398, BayesDel score -0.091, and SpliceAI predicts no splice impact (max delta = 0.00), meeting BP4 (supporting benign).

The variant is absent from ClinVar and has no published functional data. No papers were identified that mention NM_001127208.2:c.5666C>T specifically.

The variant has been observed in COSMIC (COSV54425537, n=4) as a somatic finding in cancer but lacks germline functional characterization.

PVS1 is not applicable (missense variant, not a null variant). PS1, PM5, and BP7 are not applicable due to lack of same-residue comparators or variant type mismatch.

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	This is a missense variant (p.Pro1889Leu). It does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework assessment is not applicable.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant at the same amino acid position (Pro1889) has been identified in ClinVar. The variant is absent from ClinVar entirely.	clinvar
PS2	Not assessed	No de novo data (with confirmed paternity and maternity) are available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for this variant. In silico predictors are inconsistent: REVEL score is 0.398 (below 0.5 pathogenicity threshold) and BayesDel score is -0.091 (benign-leaning). OncoKB classifies this variant as having unknown oncogenic effect with no variant-specific curated functional evidence.	revel bayesdel oncokb
PS4	Not assessed	No case-control data comparing variant prevalence in affected individuals versus controls are available.
PS5	Not assessed	No data are available regarding an alternate molecular basis for disease in a patient carrying this variant.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot. The variant (Pro1889Leu) is located in the C-terminal region of TET2 but has not been identified within a recognized functional domain where pathogenic missense variants cluster without benign variation.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 (0/155,736 alleles) and gnomAD-Canada (0 alleles). In gnomAD v4.1, it is observed at an allele frequency of 6.45×10⁻⁷ (1/1,551,522 alleles), well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (Pro1889) comparator variants classified as pathogenic were identified in ClinVar. PM5 candidate harvesting returned zero candidates.	pm5_candidates
PM6	Not assessed	No de novo data (without paternity/maternity confirmation) are available for this variant.
PP1	Not assessed	No cosegregation data in affected family members are available.
PP2	Not met	TET2 is not recognized as a gene with a low rate of benign missense variation. TET2 is frequently mutated in hematologic malignancies and population databases, and the established germline disease mechanism involves loss-of-function variants (including both truncating and missense). PP2 is not applicable in this context.	gnomad_v2 gnomad_v4 oncokb
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.398 (below the 0.5 pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice impact (max delta = 0.00). No HCI prior score is available for TET2.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess specificity for TET2-related disease.
PP5	Not met	No reputable source (ClinVar, published literature) has reported this variant as pathogenic. The variant is absent from ClinVar, and OncoKB classifies it as having unknown oncogenic effect.	clinvar oncokb
BA1	Not met	This variant has an allele frequency of 6.45×10⁻⁷ (0.00006%) in gnomAD v4.1, far below the 1% BA1 threshold. It does not meet the stand-alone benign population frequency criterion.	gnomad_v2 gnomad_v4
BS1	Not met	This variant has an allele frequency of 6.45×10⁻⁷ in gnomAD v4.1, far below the 0.3% BS1 threshold. The variant is too rare to meet BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults at an age when fully penetrant disease would be expected.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant. Computational predictions alone (BayesDel -0.091, REVEL 0.398) are insufficient to meet BS3.	bayesdel revel
BS4	Not assessed	No segregation data in affected family members are available to assess lack of cosegregation with disease.
BP1	Not met	While TET2 germline disease is associated with loss-of-function variants, the published literature describes both truncating and missense germline variants (PMID:36066697, PMID:40031954). There is insufficient evidence that TET2 disease is primarily caused by truncating variants to the exclusion of missense variants. BP1 cannot be applied.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a known pathogenic variant for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence suggest this variant has no significant impact on the gene product. REVEL score is 0.398 (below the pathogenic threshold), BayesDel score is -0.091 (benign-leaning), and SpliceAI predicts no splice alteration (max delta = 0.00). Three independent in silico tools converge on a neutral or benign prediction.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a case carrying this variant.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	This is a missense variant (c.5666C>T, p.Pro1889Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

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