NM_001127208.2:c.2152delC is a frameshift deletion predicted to result in premature termination at codon 751 (p.Leu718PhefsTer33) in TET2, a gene for which heterozygous germline loss-of-function variants are an established cause of an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy.1 This variant is absent from gnomAD population databases (v2.1 exomes, v4.1 exomes/genomes, and gnomAD-Canada v1.0), indicating it is not a common benign polymorphism and supporting evidence for rarity in the general population.2 Under the generic ACMG/AMP 2015 classification framework, application of PVS1 (Very Strong) for a null variant in a gene where loss of function is a known disease mechanism, together with PM2 (Moderate) for absence from population databases, yields a Likely Pathogenic classification (1 Very Strong + 1 Moderate).3
TET2
Final classification
Likely Pathogenic
PVS1PM2
TET2
c.2152del
p.Leu718PhefsTer33
This variant
NM_001127208.2:c.2152delC is a frameshift deletion predicted to result in premature termination at codon 751 (p.Leu718PhefsTer33) in TET2, a gene for which heterozygous germline loss-of-function variants are an established cause of an autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy.
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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
TET2 c.2152del
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
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 · 2 applied · 18 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.2152delC is a frameshift deletion predicted to produce premature termination at codon 751 (p.Leu718PhefsTer33). TET2 has an established loss-of-function disease mechanism for germline disease: heterozygous germline TET2 loss-of-function variants are associated with autoimmune lymphoproliferative syndrome-like phenotype and hematologic malignancy. The variant is in exon 3 of 11; the premature termination codon is >55 nucleotides upstream of the last exon-exon junction, so nonsense-mediated decay is expected. Under the ClinGen SVI PVS1 generic framework (PMC6185798), frameshift variants in genes with established LOF disease mechanism are assigned PVS1 at Very Strong strength.
Frameshift null variant (c.2152delp.Leu718PhefsTer33) predicted to trigger NMDTET2 germline loss-of-function established as disease mechanism (PMIDs: 36066697
✓
PM2
moderate
Pathogenic
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Under generic ACMG/AMP standards, PM2 is met when a variant is absent from or at very low frequency (<0.1%) in population databases.
Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0
Assessed · not applied
· 17 not met · 1 not assessed
Pathogenic
PS2
No de novo occurrence of NM_001127208.2:c.2152delC has been reported, and maternity/paternity confirmation data are absent from all reviewed sources.
PS3
No well-established functional studies of NM_001127208.2:c.2152delC were identified.
PS4
This variant is absent from gnomAD and ClinVar and has not been observed in affected individuals in any reviewed publication.
PM1
The variant at codon 718 lies N-terminal to the TET2 catalytic domain (residues 1129-1936) and is not located in a mutational hotspot or well-characterized critical functional domain free of benign variation.
PM6
No de novo observation of NM_001127208.2:c.2152delC has been reported with confirmed maternity and paternity in any reviewed publication or database.
PP1
No cosegregation data are available for this variant.
PP3
REVEL and BayesDel scores are not available for this deletion variant (not an SNV).
PP4
No patient phenotype or clinical presentation data are available for review.
PP5
No reputable clinical diagnostic laboratory has reported this variant as pathogenic.
Benign
BA1
The variant is absent from gnomAD (allele frequency 0), which is far below the BA1 threshold of >1% population frequency.
BS1
The variant is absent from gnomAD (allele frequency 0), which does not meet the BS1 threshold of >0.3% population frequency.
BS2
BS2 is met when a variant is observed in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
No well-established functional studies of NM_001127208.2:c.2152delC showing no damaging effect on protein function or splicing were identified in the reviewed literature.
BS4
No cosegregation data are available to demonstrate lack of segregation with disease in affected families.
BP2
No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP4
BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product.
BP5
No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6
No reputable source has reported this variant as benign.
N/A · 7
PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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 = 0.04).
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment