PVS1 (strong): NM_001127208.2:c.3765C>G is a nonsense variant (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay. TET2 loss of function is an established germline disease mechanism, with heterozygous LoF variants causing an ALPS-like phenotype with lymphoma predisposition.1 PM1 (moderate): p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, crystallographically resolved at 2.02 Å). Position 1255 lies in the Cys-rich domain adjacent to the critical L1 DNA-interacting loop. This truncation removes the C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation.2 PM2 (supporting): The variant is absent from gnomAD v2.1 and present at an extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, no homozygotes), well below the 0.1% threshold.3 Overall classification: 1 strong (PVS1) + 1 moderate (PM1) + 1 supporting (PM2) meets the ACMG/AMP threshold for Likely Pathogenic.4
TET2
Final classification
Likely Pathogenic
TET2 c.3765C>G · p.Tyr1255Ter
TET2
PVS1 (strong): NM_001127208.2:c.3765C>G is a nonsense variant (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay. TET2 loss of function is an established germline disease mechanism, with heterozygous LoF variants causing an ALPS-like phenotype with lymphoma predisposition.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM1 moderate, PM2 supporting; combination = 1 strong + 1 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PVS1PM1PM2
Likely Pathogenic
TET2 c.3765C>G
PVS1 + PM1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_context
4
generic_acmg_combination_rules
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
strong
Pathogenic
Nonsense variant NM_001127208.2:c.3765C>G (p.Tyr1255Ter) in exon 6 of 11, predicted to undergo nonsense-mediated decay, in a gene where loss of function is an established germline disease mechanism supported by multiple publications (heterozygous germline TET2 LoF variants cause an ALPS-like phenotype with lymphoma predisposition, PMID:36066697, PMID:40031954). Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at strong strength.
Nonsense variant p.Tyr1255Ter in exon 6 of 11 exonsNMD predictedTET2 loss of function is an established germline disease mechanism (heterozygous germline LoF variants associated with ALPS-like phenotype and hematologic malignancy)
✓
PM1
moderate
Pathogenic
Variant p.Tyr1255Ter is located within the well-characterized TET2 catalytic domain (residues 1129-1936, structurally resolved at 2.02 Å resolution in PMID:24315485). Position 1255 lies in the Cys-rich domain immediately adjacent to the L1 DNA-interacting loop (residues 1256-1273) that is critical for DNA binding and catalytic activity. The truncation at Y1255 removes the entire C-terminal DSBH catalytic domain essential for 5-methylcytosine oxidation. The TET2 catalytic domain is a well-established functional domain whose disruption is associated with myeloid malignancies.
PMID:24315485 — crystal structure defines TET2 catalytic domain as residues 1129-1936Y1255 is within the Cys-rich domain near L1 DNA-interacting loop (residues 1256-1273)PMID:21057493 — confirms TET2 catalytic function in 5mC-to-5hmC conversion and establishes functional importance of the catalytic domain
✓
PM2
supporting
Pathogenic
Variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.29e-06, 2/1,551,546 alleles, 0 homozygotes; grpmax FAF=2.9e-07), well below the 0.1% PM2 threshold for non-VCEP generic ACMG application.
Absent from gnomAD v2.1gnomAD v4.1: AF=1.29e-06 (2/1551
Assessed · not applied
Pathogenic
PS2
No de novo data for this variant is available in the case materials or literature reviewed.
PS3
No experimental functional data exists for the specific variant p.Tyr1255Ter or for a systematically characterized residue range that includes position 1255.
PS4
No case-control data or proband counts are available for this variant.
PM5
No pathogenic missense variant at codon 1255 was identified.
PM6
No de novo data (with confirmed maternity and paternity) is available for this variant.
PP1
No co-segregation data or pedigree information is available for this variant.
PP4
No patient phenotype or clinical history data were provided in the case materials.
PP5
Variant is absent from ClinVar.
Benign
BA1
Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 1% BA1 threshold.
BS1
Allele frequency in gnomAD v4.1 is 1.29e-06, far below the 0.3% BS1 threshold for generic ACMG application.
BS2
No homozygotes are observed in gnomAD v4.1 (0 homozygotes out of 1,551,546 alleles).
BS3
No in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4
No segregation data are available.
BP2
No observation of this variant in trans with a known pathogenic variant for TET2-related disease.
BP5
No evidence that this variant was observed in a case with an alternate molecular basis for disease.
BP6
Variant is absent from ClinVar.
N/A · 9
PS1 · PM3 · PM4 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.28904e-06; MAF= 0.00013%, 2/1551546 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.74378e-06; MAF= 0.00017%, 2/1146936 alleles, homozygotes = 0); grpmax FAF= 2.9e-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
0.00013%
· 2 / 1,551,546
0 hom · FAF 2.9e-05%
0 hom · FAF 2.9e-05%
European (non-Finnish) 2 / 1,146,936 |
0.00017% |
+ 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 = 0.05). BayesDel score = 0.023797.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54400069, n = 5 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2.
Searched
c.3765C>Gp.Tyr1255TerY1255*Tyr12551255
Found
Characterizes TET2 as a 5-methylcytosine dioxygenase that converts 5mC to 5hmC. Functional assays tested specific missense mutations (H1302Y, D1304A, H1802R, H1802Q, P1287S, W1211R, C1834D, R1817S/M) in the TET2 catalytic domain. Confirms that mutations in Fe(II)-chelating and 2OG-binding residues abolish catalytic activity.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Variant not specifically tested. Provides domain-level evidence that TET2 catalytic domain is functionally critical, supporting PM1 but not PS3.
HEK293T cells expressing Tet2 mutants H1802R and H1802Q showed greatly diminished 5-hmC staining and no loss of 5-mC staining, consistent with participation of this residue in catalysis.
Location Results section; Figure 1; Supplementary Figures 1-4 · Context HEK293T cells, Myc-tagged murine Tet2 overexpression, immunocytochemistry for 5hmC/5mC, dot blot assays · full text
Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation.
Searched
c.3765C>Gp.Tyr1255TerY1255*Tyr12551255
Found
Reports the crystal structure of human TET2 catalytic domain (residues 1129-1936) bound to methylated DNA at 2.02 Å resolution. Defines the Cys-rich and DSBH domains, DNA-interacting loops L1 (residues 1256-1273) and L2 (residues 1288-1312), and Fe(II)/2OG-chelating residues. Residue Y1255 is located at the boundary of the Cys-rich domain immediately before the L1 DNA-binding loop.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Variant not specifically tested. Provides structural domain characterization confirming that the TET2 catalytic domain (1129-1936) is essential for function, supporting PM1 at domain level.
Loop L2 (residues 1288–1312) is inserted into the minor groove of DNA, and L1 (residues 1256–1273) supports DNA on the other side.
Location Results: Structure Determination; Overall Structure; Figures 1, 3, 4 · Context X-ray crystallography, HEK293T cells for activity assays of mutant constructs, LC-MS/MS for in vitro enzymatic activity · full text
Sources & reference links