Variant classification summary

NM_001127208.2:c.2193A>G

TET2 · NP_001120680.1:p.(Gln731=) · NM_001127208.2

GRCh37: chr4:106157292 A>G · GRCh38: chr4:105236135 A>G

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Gln731=)

gnomAD AF

1.2390606433450672e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 1.24e-06 (2/1,614,126 alleles), far below the 0.1% rare threshold.

2

BP7 (Supporting): synonymous variant (p.(Gln731=)) outside the splice consensus with SpliceAI maximum delta score 0.001, predicting no splicing disruption.

3

Overall: VUS - one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP7) do not satisfy any generic ACMG/AMP 2015 combination threshold for Pathogenic, Likely Pathogenic, Benign, or Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback requires combinations such as 2 PS, 1 PVS1+1 PM, 3 PM, 1 BS+1 BP, or 2 BS; with only PM2 supporting and BP7 supporting met, none are satisfied, so the variant is VUS.

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 synonymous variant (p.(Gln731=)) triggers no null-variant mechanism such as nonsense-mediated decay or canonical splice disruption.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the variant produces no amino acid change, so there is no altered residue to compare with a previously pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo observation with confirmed absence of the variant in both biological parents was documented.
PS3	Not assessed	Not assessed: insufficient evidence was available - no functional or enzymatic assay data for this variant were provided.
PS4	Not assessed	Not assessed: no case-control data or affected-individual counts for this exact variant were available.
PM1	N/A	Not applicable: the variant is synonymous, so no altered residue exists to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 1.24e-06 (2/1,614,126 alleles), far below the 0.1% rare threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no evidence of a pathogenic variant in trans, affected-proband observations, or phase information was available.
PM4	N/A	Not applicable: the variant is synonymous, so no protein length change occurs for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a previously pathogenic missense variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no presumed de novo occurrence or parental testing results were documented.
PP1	Not assessed	Not assessed: no segregation data from affected or unaffected relatives were available.
PP2	N/A	Not applicable: the variant is synonymous, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI maximum delta score 0.001 shows no splicing effect, and missense predictors do not apply to a synonymous change.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnosis was available for evaluation.
PP5	Not met	Not met: ClinVar's only assertion is a single-submitter Likely benign laboratory classification, not an expert-panel pathogenic one.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency 0.000124% is far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS1	Not met	Not met: the maximum subpopulation allele frequency 0.00327% is far below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS2	Not met	Not met: the variant has zero homozygotes in gnomAD v4.1 and v2.1, and no healthy-adult observations were provided.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: insufficient evidence was available - no functional assay demonstrating normal activity was provided.
BS4	Not assessed	Not assessed: no family or genotype-phenotype discordance data were available.
BP1	N/A	Not applicable: the variant is synonymous, so no missense change exists to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no in-trans observations with a pathogenic variant or phase data were available.
BP3	N/A	Not applicable: the variant is synonymous and does not alter protein length in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: missense predictors cannot evaluate a synonymous change, and the SpliceAI result is already counted under BP7.
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or pathogenic variant explaining a disease presentation was documented.
BP6	Not met	Not met: ClinVar's Likely benign assertion is a single-submitter laboratory classification, not an expert-panel one.	clinvar
BP7	Met	Met (supporting): synonymous variant outside the splice consensus with SpliceAI maximum delta score 0.001, predicting no splicing disruption.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.