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).1 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.2 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.3
TET2
Final classification
VUS
TET2 c.5920A>C · p.Arg1974=
TET2
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
TET2 c.5920A>C
PM2
→
VUS
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1.gnomAD v4.1: AF=1.93e-06 (3/1551
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same amino acid position as an established pathogenic variant.
PS2
No de novo data (with confirmed paternity and maternity) are available for this variant.
PS3
No well-established in vitro or in vivo functional studies have been identified for NM_001127208.2:c.5920A>C.
PS4
No case-control studies comparing variant prevalence in affected individuals versus controls are available.
PM1
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.
PM6
No de novo occurrence data (without confirmation of paternity and maternity) are available for this variant.
PP1
No cosegregation data with disease in multiple affected family members are available.
PP3
Multiple lines of computational evidence are required to support a deleterious effect.
PP4
No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for TET2-related disease.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 1% threshold for BA1.
BS1
The variant allele frequency in gnomAD v4.1 is 0.00019% (3/1,551,980 alleles), far below the 0.3% threshold for BS1.
BS2
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
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
No family segregation data demonstrating lack of cosegregation with disease are available.
BP2
No data are available on whether this variant has been observed in trans with a known pathogenic TET2 variant.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
No data are available on whether this variant has been observed in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
BP7
BP7 requires a synonymous variant for which splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved.
N/A · 7
PVS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.93301e-06; MAF= 0.00019%, 3/1551980 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.61541e-06; MAF= 0.00026%, 3/1147046 alleles, homozygotes = 0); grpmax FAF= 7e-07.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,551,980
0 hom · FAF 7e-05%
0 hom · FAF 7e-05%
European (non-Finnish) 3 / 1,147,046 |
0.00026% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
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.
Sources & reference links