NM_001127208.2:c.822del is a frameshift deletion in exon 3 of TET2, predicted to cause a premature termination codon (p.Asn275IlefsTer18) with expected nonsense-mediated decay, meeting PVS1 at very strong strength. TET2 loss-of-function is an established germline disease mechanism associated with ALPS-like phenotype and hematologic malignancy susceptibility.1 This variant is present in gnomAD at extremely low frequency (AF=0.00167% in v4.1, 0.00160% in v2.1; no homozygotes), meeting PM2 at supporting strength.2 SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00), but REVEL and BayesDel are not available for this deletion variant, so PP3 is not met.3 This variant has been reported as Pathogenic in ClinVar by a single clinical laboratory (1-star review status). PP5 requires a 3-star expert panel review and is not met. The variant is absent from COSMIC as a somatic observation? No: COSMIC reports this variant in n=30 somatic cancer samples (COSV54404867). OncoKB classifies the variant as Likely Oncogenic with Likely Loss-of-function effect.4
TET2
Final classification
VUS
TET2 c.822del · p.Asn275IlefsTer18
TET2
NM_001127208.2:c.822del is a frameshift deletion in exon 3 of TET2, predicted to cause a premature termination codon (p.Asn275IlefsTer18) with expected nonsense-mediated decay, meeting PVS1 at very strong strength. TET2 loss-of-function is an established germline disease mechanism associated with ALPS-like phenotype and hematologic malignancy susceptibility.
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 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
TET2 c.822del
PVS1 + PM2
→
VUS
1
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗PMID:36066697 ↗
Gene diagram
· NM_001127208.2 · variants mapped to exon structure
TET2
NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 22 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_001127208.2:c.822del is a frameshift variant in exon 3 of 11, predicted to cause a premature termination codon at position 292 (NP_001120680.1:p.(Asn275IlefsTer18)) with expected nonsense-mediated decay. TET2 has an established loss-of-function disease mechanism in the germline context, associated with an ALPS-like phenotype and hematologic malignancy susceptibility. Under ClinGen SVI PVS1 recommendations (PMC6185798), a null variant in a gene where LOF is a known mechanism of disease meets PVS1 at very strong strength.
Frameshift variant creating premature termination codon at p.Asn275IlefsTer18 in exon 3 of 11PTC is >50-55 nucleotides upstream of the next exon-exon junction (exon 3 is large: c.-46 to c.3409)NMD expected
✓
PM2
supporting
Pathogenic
This variant is present in gnomAD at extremely low frequency (v2.1: AF=0.0016%, 4/250,288 alleles; v4.1: AF=0.00167%, 27/1,613,714 alleles; highest subpopulation AF=0.00327% in South Asian, gnomAD v2.1). This frequency is well below the 0.1% threshold for PM2 under generic ACMG/AMP rules. No homozygotes have been observed.
gnomAD v2.1: AF=1.598e-05 (4/250288 alleles0 homozygotes)
Assessed · not applied
Pathogenic
PS2
PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed.
PS3
PS3 requires variant-specific functional evidence.
PS4
PS4 requires the variant prevalence in affected individuals to be significantly increased compared to controls.
PM1
PM1 requires location in a critical functional domain or mutational hotspot.
PM6
PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity.
PP1
PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2
PP2 applies to missense variants in genes where missense variation is the primary pathogenic mechanism and benign missense variation is rare.
PP3
PP3 requires multiple lines of computational evidence supporting a deleterious effect.
PP4
PP4 requires a patient phenotype or family history highly specific for a disease with a single genetic etiology.
PP5
PP5 requires a reputable source to have classified the variant as pathogenic with supporting evidence.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
BS2 requires observation of the variant in a healthy adult individual for a disorder with full penetrance expected at an early age, in the appropriate zygosity state.
BS3
BS3 requires well-established functional studies showing no damaging effect.
BS4
BS4 requires lack of segregation of the variant with disease in affected family members.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP3
BP3 applies to in-frame deletions or insertions in repetitive regions without known function.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on the gene product.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have classified the variant as benign.
BP7
BP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation.
N/A · 3
PS1 · PM4 · PM5
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.67316e-05; MAF= 0.00167%, 27/1613714 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37975e-05; MAF= 0.00338%, 1/29588 alleles, homozygotes = 0); grpmax FAF= 1.107e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.59816e-05; MAF= 0.00160%, 4/250288 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27097e-05; MAF= 0.00327%, 1/30572 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0017%
· 27 / 1,613,714
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
Ashkenazi Jewish 1 / 29,588 |
0.0034% |
East Asian 1 / 44,842 |
0.0022% |
South Asian 2 / 91,068 |
0.0022% |
European (non-Finnish) 20 / 1,179,890 |
0.0017% |
Remaining individuals 1 / 62,484 |
0.0016% |
European (Finnish) 1 / 64,006 |
0.0016% |
African/African American 1 / 74,906 |
0.0013% |
+ 3 not observed (Admixed American, Amish, Middle Eastern)
gnomAD v2.1
0.0016%
· 4 / 250,288
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
South Asian 1 / 30,572 |
0.0033% |
Admixed American 1 / 34,468 |
0.0029% |
European (non-Finnish) 2 / 112,998 |
0.0018% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 1936676)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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; COSV54404867, n = 30 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
36066697 ↗
Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.
CLINVAR