NM_001127208.2:c.1413C>T

TET2 · NP_001120680.1:p.(Ser471=) · NM_001127208.2

GRCh37: chr4:106156512 C>T · GRCh38: chr4:105235355 C>T

Gene: TET2 Transcript: NM_001127208.2

Final call

VUS

PM2 supporting BP7 supporting benign

Variant details

Gene

TET2

Transcript

NM_001127208.2

Protein

NP_001120680.1:p.(Ser471=)

gnomAD AF

5.576090714322003e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001127208.2:c.1413C>T (p.Ser471=) is a synonymous variant in TET2 at extremely low population frequency (gnomAD v2.1 AF=0.00142%, 4/282,248 alleles; v4.1 AF=0.00056%, 9/1,614,034 alleles), meeting PM2 at supporting level.

SpliceAI predicts no splicing impact (max delta=0.00), meeting BP7 (supporting benign) for a synonymous variant without predicted splice alteration.

ClinVar contains a single submission classifying this variant as Likely benign (Ambry Genetics, criteria provided), though no expert panel review exists. PS5 and PP5 are not met as the classification is not pathogenic.

No variant-specific literature, functional studies, de novo observations, or segregation data were identified. Multiple criteria could not be assessed due to absence of evidence.

The pathogenic evidence (PM2 supporting) and benign evidence (BP7 supporting_benign) are balanced and of equivalent weight. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as 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	Synonymous variant (p.Ser471=) does not meet null-variant criteria. PVS1 requires nonsense, frameshift, canonical splice, initiation codon, or exon deletion variants per ClinGen PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	Synonymous variant produces no amino acid change. PS1 requires the same amino acid change as a known pathogenic variant, which is not applicable to synonymous substitutions.
PS2	Not assessed	No de novo evidence identified. ClinVar submission audit and literature search yielded no de novo observations for this variant.
PS3	Not assessed	No functional study data available for this variant. REVEL and BayesDel scores not available for synonymous variants. No variant-specific functional evidence identified in ClinVar submissions or literature.
PS4	Not assessed	No case-control or affected-cohort enrichment data available. ClinVar contains a single submitter classification (Ambry Genetics, Likely benign) from clinical testing but no affected-person counts or case-control comparisons.	clinvar
PS5	Not met	PS5 requires a reputable source to have classified the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign (Ambry Genetics, criteria provided, single submitter). No expert panel or multi-submitter pathogenic classification exists.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot, nor in a critical functional domain where all missense variants are pathogenic. Hotspot analysis: residue_significant=false, exact variant not listed.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles), grpmax FAF=7.04e-06. Absent from gnomAD-Canada. Frequency is well below the 0.1% PM2 threshold for a rare disease variant.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Synonymous variant (p.Ser471=) produces no amino acid change. PM5 requires a different missense change at the same residue as a known pathogenic missense variant, which is not applicable to synonymous substitutions.	pm5_candidates
PM6	Not assessed	No de novo data available. No de novo observations identified in ClinVar submissions or literature for this variant.
PP1	Not assessed	No family segregation data available for this variant.
PP2	N/A	Synonymous variant, not missense. PP2 is applicable only to missense variants in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00). REVEL and BayesDel scores are not available for this synonymous variant. No in silico tool predicts pathogenicity.	spliceai
PP4	Not assessed	No detailed phenotype data available for individuals carrying this variant. Single ClinVar submission from Ambry Genetics does not include phenotype specifics.	clinvar
PP5	Not met	PP5 requires a reputable source to have classified the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign (Ambry Genetics, single submitter). No expert panel classification as pathogenic exists.	clinvar
BA1	Not met	BA1 threshold is >1% allele frequency. gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles). Both are well below the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 threshold is >0.3% allele frequency. gnomAD v2.1 AF=0.00142% and gnomAD v4.1 AF=0.00056% are both well below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Variant is present in gnomAD at very low frequency (4 alleles v2.1, 9 alleles v4.1) but the health status of these individuals is unknown. TET2 germline disease (ALPS-like phenotype with hematologic malignancy) has variable penetrance; observation in population databases alone is insufficient to confirm observation in a confirmed healthy adult with full expected penetrance.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies demonstrating no deleterious effect for this variant. No variant-specific functional evidence available.
BS4	Not assessed	No family segregation data available. Lack of segregation in affected family members cannot be assessed without pedigree data.
BP1	N/A	Synonymous variant, not missense. BP1 applies specifically to missense variants in a gene where a truncating mechanism is the primary cause of disease.
BP2	Not assessed	No data on observations of this variant in trans with a pathogenic variant. TET2 germline disease follows an autosomal dominant (heterozygous LoF) model; BP2 primarily applies to recessive disorders.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI (max delta=0.00) is available, which is a single line of evidence. REVEL, BayesDel, and HCI prior are not available for this variant. Conservation data is not available. A single computational datum is insufficient to satisfy the 'multiple lines' requirement of BP4.	spliceai
BP5	Not met	BP5 applies when a variant has not been observed in affected individuals despite being present in a case with an alternate molecular basis. This variant has been observed in a clinical testing context (ClinVar submission SCV005954740, Ambry Genetics), indicating it has been encountered in a diagnostic setting. BP5 is not met.	clinvar
BP6	Not met	BP6 applies when a reputable source reports the variant as benign and the evidence is not available for independent evaluation. Independent evaluation has been performed using available evidence (gnomAD, SpliceAI, ClinVar). The sole ClinVar classification is Likely benign from a single submitter (Ambry Genetics) without expert panel review; this does not independently meet the BP6 threshold.	clinvar
BP7	Met	This is a synonymous variant (p.Ser471=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no donor gain, donor loss, acceptor gain, or acceptor loss). No evidence of cryptic splice site creation. The variant meets BP7 criteria for a silent variant without predicted splice impact.	spliceai
BP3	N/A	Variant is not an in-frame insertion/deletion in a non-repeat region.
PM3	N/A	TET2 germline disease follows an autosomal dominant model (heterozygous LoF); PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant.
PM4	N/A	Variant is a single-nucleotide synonymous substitution, not an in-frame deletion/insertion or stop-loss variant.

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.