Variant classification summary

NM_001127208.2:c.2119G>A

TET2 · NP_001120680.1:p.(Ala707Thr) · NM_001127208.2

GRCh37: chr4:106157218 G>A · GRCh38: chr4:105236061 G>A

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting BP1 supporting BP4 moderate

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Ala707Thr)

gnomAD AF

6.195917386115941e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1 and gnomAD-Canada, with only 1 alternate allele among 1,613,966 in gnomAD v4.1.

2

BP1 (Supporting): TET2 germline disease is driven by loss-of-function variants, favoring a benign interpretation for this missense change.

3

BP4 (Moderate): REVEL score 0.095 falls at or below the <=0.183 benign-predicting threshold.

4

Overall: VUS — PM2 (supporting), BP1 (supporting), and BP4 (moderate) satisfy no generic ACMG/AMP 2015 combining rule for Pathogenic, Likely Pathogenic, Benign, or Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules: the adjudicated criteria set (PM2 supporting, BP1 supporting, BP4 moderate) does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, so the variant defaults to Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: this missense substitution does not trigger a null-variant mechanism such as nonsense-mediated decay, truncation, or canonical splice disruption.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no pathogenic alternate nucleotide change producing the same p.Ala707Thr amino acid substitution was identified.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence or confirmed parental testing was documented.
PS3	Not assessed	Not assessed: no functional assay data addressing TET2 p.Ala707Thr were available.
PS4	Not assessed	Not assessed: no case-control or disease-prevalence data for this variant were available.
PM1	Not met	Not met: no hotspot or somatic-recurrence signal was found, and residue 707 lies outside TET2's established catalytic domains.
PM2	Met	Met (supporting): absent from gnomAD v2.1 and gnomAD-Canada, with only 1 alternate allele among 1,613,966 in gnomAD v4.1.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband observations, phase, or inheritance data were documented.
PM4	N/A	Not applicable: this missense substitution causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 707 established as pathogenic was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no suspected de novo occurrence without confirmed parental relationships was reported.
PP1	Not assessed	Not assessed: no segregation or cosegregation observations were documented.
PP2	Not met	Not met: TET2 germline disease is mediated by loss-of-function variants, not by recurrent missense changes.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.095 vs the >=0.644 pathogenic supporting threshold.	revel spliceai
PP4	Not assessed	Not assessed: no patient phenotype or clinical information was provided.
PP5	N/A	Not applicable: the ClinVar record has only a single 'uncertain significance' submission, with no expert-panel pathogenic assertion.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 6.2e-07 (1/1,613,966) vs the >1% stand-alone benign threshold.	gnomad_v4
BS1	Not met	Not met: highest population allele frequency 8.5e-07 vs the >0.3% benign threshold.	gnomad_v4
BS2	Not met	Not met: zero homozygotes in gnomAD v4.1, and the variant is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data were available to establish normal, wild-type-like function.
BS4	Not assessed	Not assessed: no unaffected relatives were tested for the variant.
BP1	Met	Met (supporting): TET2 germline disease is driven by loss-of-function variants, favoring benignity for this missense change.	pvs1_gene_context
BP2	Not assessed	Not assessed: no data show the variant in cis or trans with a pathogenic variant.
BP3	N/A	Not applicable: this missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (moderate): REVEL score 0.095 vs the <=0.183 benign-predicting threshold.	revel spliceai
BP5	Not assessed	Not assessed: no information on an alternative molecular diagnosis was available.
BP6	N/A	Not applicable: the ClinVar record has only a single 'uncertain significance' submission, with no expert-panel benign assertion.	clinvar
BP7	N/A	Not applicable: defined for synonymous variants; this is a missense substitution.	generic_acmg_combination_rules

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