NM_001127208.2:c.5920A>C

TET2 · NP_001120680.1:p.(Arg1974=) · NM_001127208.2

GRCh37: chr4:106197587 A>C · GRCh38: chr4:105276430 A>C

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Arg1974=)

gnomAD AF

1.933014600703617e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.5920A>C (p.Arg1974=) is a synonymous variant in TET2. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,551,980 alleles, 0 homozygotes), meeting PM2 at supporting level. No other pathogenic or benign criteria are met. Per generic ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting criterion (PM2) is insufficient to reach Likely Pathogenic or Likely Benign classification thresholds. This variant is classified as a Variant of Uncertain Significance (VUS).

SpliceAI predicts no splice impact (max delta score = 0.00). Computational predictors REVEL and BayesDel are unavailable for this synonymous variant. Conservation data are unavailable, precluding application of BP7 despite the clean SpliceAI result.

This variant is absent from ClinVar and has not been reported in any publication identified through literature search. TET2 germline loss-of-function variants are associated with an ALPS-like phenotype and hematologic malignancy predisposition, but the clinical significance of synonymous variants in this gene remains uncertain.

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.5920A>C is a synonymous variant (p.Arg1974=) with SpliceAI max delta score of 0.00 and no predicted splice impact. It does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) and is therefore not eligible for PVS1 under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	Not assessed	PS1 requires a different nucleotide change at the same amino acid position as an established pathogenic variant. This variant is synonymous (no amino acid change), and no pathogenic variants at residue Arg1974 are available for comparison.
PS2	Not assessed	No de novo data (with confirmed paternity and maternity) are available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies have been identified for NM_001127208.2:c.5920A>C.
PS4	Not assessed	No case-control studies comparing variant prevalence in affected individuals versus controls are available.
PS5	Not assessed	No reputable source has independently classified this variant as pathogenic. The variant is absent from ClinVar and no published literature reports it as pathogenic.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot in TET2, and the affected residue (Arg1974) has not been identified as a critical functional domain with a paucity of benign variation.
PM2	Met	NM_001127208.2:c.5920A>C is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (AF=0.00019%, 3/1,551,980 alleles, 0 homozygotes; grpmax FAF=7e-07), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to variants observed in trans with a pathogenic variant in recessive disorders. TET2 germline disease is not recessively inherited; this criterion is not applicable.
PM4	N/A	PM4 applies to non-repeat indels or stop-loss variants causing protein length changes. This is a single-nucleotide substitution; PM4 is not applicable.
PM5	N/A	PM5 requires a novel missense change at the same amino acid residue as an established pathogenic missense variant. NM_001127208.2:c.5920A>C is synonymous (p.Arg1974=) with no amino acid change, so no pathogenic comparator at this residue can be evaluated.	pm5_candidates
PM6	Not assessed	No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant.
PP1	Not assessed	No cosegregation data with disease in multiple affected family members are available.
PP2	N/A	PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. This is a synonymous variant and does not qualify for PP2 assessment.
PP3	Not met	Multiple lines of computational evidence are required to support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00), and REVEL, BayesDel, and HCI prior scores are all unavailable for this variant. No computational evidence supports a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for TET2-related disease.
PP5	Not assessed	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and is not classified in any published literature.	clinvar
BA1	Not met	The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 1% threshold for BA1. The variant does not qualify as a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 0.3% threshold for BS1. The variant is also absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available on whether the 3 individuals carrying this variant in gnomAD v4.1 are healthy adults, which would be required to apply BS2 (observed in a healthy adult individual for a recessive/highly penetrant disorder with full penetrance expected at an early age).
BS3	Not assessed	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.
BS4	Not assessed	No family segregation data demonstrating lack of cosegregation with disease are available.
BP1	N/A	BP1 applies specifically to missense variants in genes where a truncating mechanism is the primary cause of disease. This is a synonymous variant and does not qualify for BP1 assessment.
BP2	Not assessed	No data are available on whether this variant has been observed in trans with a known pathogenic TET2 variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. Only one line is available: SpliceAI predicts no splice impact (max delta=0.00). REVEL, BayesDel, and conservation data are all unavailable, precluding a multi-line benign computational assessment.	spliceai
BP5	Not assessed	No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not assessed	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	Not met	BP7 requires a synonymous variant for which splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. SpliceAI confirms no predicted splice impact (max delta=0.00), satisfying the first condition. However, nucleotide-level conservation data (e.g., phyloP, GERP) are unavailable, preventing confirmation that the nucleotide is not highly conserved — a required component of BP7.	spliceai

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