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

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

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

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).

SpliceAI ↗

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

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