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TET2
Final classification
VUS
PM2BP7
TET2
c.2193A>G
p.Gln731=
synonymous · exon 3
Gene context NCBI Gene ↗ OncoKB ↗

TET2 encodes an enzyme that converts 5-methylcytosine to 5-hydroxymethylcytosine, a key step in active DNA demethylation that helps regulate gene expression. It is important for normal blood cell formation, and defects in the gene are associated with several myeloproliferative disorders. TET2 acts as a tumor suppressor, and its mutations are most often found in blood cancers, where loss of its function can cooperate with other mutations to promote malignancy. Mutations are also found in people with clonal hematopoiesis who have no apparent blood disease but carry an increased risk of developing hematologic cancer with aging.

This variant

This variant is a synonymous change (p.(Gln731=)) in TET2, a tumor-suppressor gene that regulates DNA demethylation and is frequently mutated in blood cancers and clonal hematopoiesis. It leaves the encoded amino acid unchanged and is predicted to have no effect on splicing, so it does not trigger the loss-of-function mechanisms associated with TET2-related disease. Because it is extremely rare in the general population but lacks functional and clinical evidence, it remains a variant of uncertain significance.

Transcript
NM_001127208.2
HGVS · transcript:coding
NM_001127208.2:c.2193A>G
GRCh38
chr4:105236135 A>G
GRCh37
chr4:106157292 A>G
Basis VUS: no TET2-specific ClinGen framework exists, so generic ACMG/AMP 2015 rules apply; the only met criteria, PM2 (supporting) and BP7 (supporting), do not reach any pathogenic or benign classification threshold. ▾
VUS: no TET2-specific ClinGen framework exists, so generic ACMG/AMP 2015 rules apply; the only met criteria, PM2 (supporting) and BP7 (supporting), do not reach any pathogenic or benign classification threshold.
Classification rationale
PM2 BP7 VUS
TET2 c.2193A>G synonymous · exon 3

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 1.24e-06 (2/1,614,126 alleles), far below the 0.1% rare threshold. BP7 (Supporting): synonymous variant (p.(Gln731=)) outside the splice consensus with SpliceAI maximum delta score 0.001, predicting no splicing disruption. Overall: VUS - one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7) do not satisfy any generic ACMG/AMP 2015 combination threshold for Pathogenic, Likely Pathogenic, Benign, or Likely Benign.

PM2 + BP7 → VUS
Gene diagram · NM_001127208.2 · variants mapped to exon structure
TET2 NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 1.24e-06 (2/1,614,126 alleles), far below the 0.1% rare threshold.
gnomAD v4.1 reports 2/1,614,126 alleles, AF 1.23906e-06, 0 homozygotes, and maximum listed subpopulation AF 1.09786e-05 in South Asian individuals.gnomAD v2.1 reports 2/250,660 alleles, AF 7.97894e-06, 0 homozygotes, and maximum listed subpopulation AF 3.26691e-05 in South Asian individuals.gnomAD-Canada v1.0 reports the variant as absent.
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
✓
BP7 supporting review Benign
Met (supporting): synonymous variant outside the splice consensus with SpliceAI maximum delta score 0.001, predicting no splicing disruption.
Variant is synonymous (p.Gln731=) and does not fall in the canonical splice consensus region per the case's PVS1 variant assessment.SpliceAI predicts no significant splice impact for this variant (max delta score = 0.001), supporting no impact on splicing consistent with BP7.
spliceai ↗
Assessed · not applied · 6 not met · 11 not assessed
Pathogenic
PS2 Not assessed: no de novo observation with confirmed absence of the variant in both biological parents was documented.
PS3 Not assessed: insufficient evidence was available - no functional or enzymatic assay data for this variant were provided.
PS4 Not assessed: no case-control data or affected-individual counts for this exact variant were available.
PM3 Not assessed: no evidence of a pathogenic variant in trans, affected-proband observations, or phase information was available.
PM6 Not assessed: no presumed de novo occurrence or parental testing results were documented.
PP1 Not assessed: no segregation data from affected or unaffected relatives were available.
PP3 Not met: SpliceAI maximum delta score 0.001 shows no splicing effect, and missense predictors do not apply to a synonymous change.
PP4 Not assessed: no patient phenotype or clinical diagnosis was available for evaluation.
PP5 Not met: ClinVar's only assertion is a single-submitter Likely benign laboratory classification, not an expert-panel pathogenic one.
Benign
BA1 Not met: gnomAD v4.1 allele frequency 0.000124% is far below the >1% BA1 threshold.
BS1 Not met: the maximum subpopulation allele frequency 0.00327% is far below the >0.3% BS1 threshold.
BS2 Not met: the variant has zero homozygotes in gnomAD v4.1 and v2.1, and no healthy-adult observations were provided.
BS3 Not assessed: insufficient evidence was available - no functional assay demonstrating normal activity was provided.
BS4 Not assessed: no family or genotype-phenotype discordance data were available.
BP2 Not assessed: no in-trans observations with a pathogenic variant or phase data were available.
BP5 Not assessed: no alternative molecular diagnosis or pathogenic variant explaining a disease presentation was documented.
BP6 Not met: ClinVar's Likely benign assertion is a single-submitter laboratory classification, not an expert-panel one.
N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23906e-06; MAF= 0.00012%, 2/1614126 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09786e-05; MAF= 0.00110%, 1/91086 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.97894e-06; MAF= 0.00080%, 2/250660 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26691e-05; MAF= 0.00327%, 1/30610 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012% · 2 / 1,614,126
0 hom
South Asian
1 / 91,086
0.0011%
European (non-Finnish)
1 / 1,179,990
8.5e-05%
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008% · 2 / 250,660
0 hom
South Asian
1 / 30,610
0.0033%
European (non-Finnish)
1 / 113,076
0.00088%
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3967698)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots