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TET2
Final classification
VUS
PVS1PM2
TET2
c.4466dup
p.Asn1489LysfsTer2
This variant

NM_001127208.2:c.4466dup (p.Asn1489LysfsTer2) is a frameshift duplication in exon 10 of TET2 predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength.

Transcript
NM_001127208.2
HGVS · transcript:coding
NM_001127208.2:c.4466dup
GRCh38
chr4:105272842 T>TA
GRCh37
chr4:106193999 T>TA
Basis 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. ▾
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.4466dup

NM_001127208.2:c.4466dup (p.Asn1489LysfsTer2) is a frameshift duplication in exon 10 of TET2 predicted to trigger nonsense-mediated decay, meeting PVS1 at very strong strength.1 This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with a single heterozygous observation in gnomAD v4.1 (1/1,550,974 alleles, AF = 0.000064%), meeting PM2 at supporting level.2

PVS1 + PM2 → VUS
1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Gene diagram · NM_001127208.2 · variants mapped to exon structure
TET2 NM_001127208.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 11 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
✓
PVS1 very strong Pathogenic
NM_001127208.2:c.4466dup is a frameshift duplication in exon 10 of 11, predicted to introduce a premature termination codon at p.(Asn1489LysfsTer2). NMD is expected as the PTC occurs well before the final exon (exon 11). TET2 loss of function is an established germline disease mechanism supported by literature (ALPS-like phenotype, hematologic malignancy). Under ClinGen SVI PVS1 framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are eligible for PVS1 at very strong strength.
Frameshift duplication creates PTC at codon 1490 (p.Asn1489LysfsTer2)PTC located in exon 10 of 11NMD is expected
pvs1_generic_framework ↗
✓
PM2 supporting Pathogenic
NM_001127208.2:c.4466dup is absent from gnomAD v2.1 and gnomAD-Canada and is present at an extremely low frequency in gnomAD v4.1 (1/1,550,974 alleles, AF = 6.45e-07). This allele frequency is well below the PM2 threshold of 0.1% for a gene where TET2 LOF variants are associated with disease.
gnomAD v2.1: absentgnomAD v4.1: 1 allele / 1550
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 11 not met · 0 not assessed
Pathogenic
PS3 No variant-specific functional studies identified for NM_001127208.2:c.4466dup.
PS4 This variant is absent from ClinVar and COSMIC and has been observed only once in gnomAD v4.1 (1/1,550,974 alleles).
PM1 This variant does not lie in a statistically significant mutational hotspot.
PP3 REVEL and BayesDel scores are unavailable for this duplication variant.
PP5 This variant has not been reported by any reputable germline classification source.
Benign
BA1 NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BA1 threshold of 1% in any population.
BS1 NM_001127208.2:c.4466dup has an allele frequency of 6.45e-07 in gnomAD v4.1, far below the BS1 threshold of 0.3% for dominant disorders.
BS2 Only one allele has been observed in gnomAD (v4.1), with no information on the clinical phenotype of that individual.
BS3 No variant-specific functional studies are available for NM_001127208.2:c.4466dup.
BP4 REVEL and BayesDel are unavailable for this duplication variant.
BP6 No reputable source has classified NM_001127208.2:c.4466dup as benign.
N/A · 14 PS1 · PS2 · PM4 · PM5 · PM6 · PP1 · PP2 · PP4 · BS4 · BP1 · BP2 · BP3 · BP5 · BP7
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= 6.44756e-07; MAF= 0.00006%, 1/1550974 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.71984e-07; MAF= 0.00009%, 1/1146810 alleles, homozygotes = 0).
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
6.4e-05% · 1 / 1,550,974
0 hom
European (non-Finnish)
1 / 1,146,810
8.7e-05%
+ 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
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
SpliceAI ↗
Functional / OncoKB screenshot
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.
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
Triaged references · 2 PMIDs not cited in assessment
21057493 ↗ Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. ONCOKB
24315485 ↗ Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. ONCOKB