TET2 c.2119G>A, p.(Ala707Thr)

Reasoning

PM2 is met at supporting strength. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is exceptionally rare in gnomAD v4.1, with only 1 alternate allele among 1,613,966 alleles, no homozygotes, and a maximum listed subpopulation AF of 8.474418273557612e-07. This is below the generic rare-variant threshold of <0.1% used when no applicable VCEP specification is available.

Rule

Generic PM2 rule: the variant is absent or extremely rare in population databases, with no homozygotes when relevant; under the generic non-VCEP operating threshold, AF <0.1% supports PM2 at supporting strength.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.
• gnomAD v4.1 reports one alternate allele among 1,613,966 total alleles (AF 6.195917386115941e-07), zero homozygotes, and highest listed subpopulation AF 8.474418273557612e-07 in European non-Finnish samples.
• The maximum observed frequency is below the generic PM2 threshold of <0.1% for a rare variant in population databases.
• No applicable TET2 VCEP or gene-specific framework was retrieved; generic ACMG/AMP fallback was therefore used.

Still missing

• The case does not provide a TET2-specific disease prevalence/penetrance-based maximum credible allele frequency or a complete ancestry-matched control dataset beyond the referenced population resources.

Sources

Reasoning

BP1 applies to a missense variant in a gene for which primarily truncating/loss-of-function variants are known to cause disease. The case's gene-level germline context (pvs1_gene_context.json) establishes that TET2 germline disease (ALPS-like phenotype, hematologic malignancy predisposition) is mediated through loss-of-function variants, with lof_mechanism_supported=true and no missense-mechanism disease evidence identified in this bundle. This truncating-predominant disease mechanism supports BP1 at supporting strength for this missense variant.

Rule

generic_ACMG_2015_BP1

Evidence considered

• pvs1_gene_context.json germline literature review (targeted TET2 germline syndrome/loss-of-function queries) supports TET2 loss-of-function as the established germline disease mechanism (lof_mechanism_supported=true), consistent with a gene where truncating variants primarily cause disease, favoring BP1 for this missense variant.

Sources

Reasoning

No governing VCEP/CSPEC was found for TET2 (generic_acmg framework), so generic ACMG/AMP computational-evidence rules apply. NM_001127208.2:c.2119G>A (p.Ala707Thr) has a REVEL score of 0.095, which falls at or below the ClinGen SVI-calibrated REVEL BP4_Moderate threshold (<=0.183) from Pejaver et al. 2022 (PMID 36413997), supporting a benign missense prediction at moderate strength. This is corroborated by SpliceAI, which predicts no splice impact for this substitution (max delta score = 0.002), consistent with a purely missense mechanism with no competing splice-disruption signal; the SpliceAI result is used only as corroborating context and is not independently counted as a second BP4 code for the same criterion.

Rule

generic_acmg_2015_revel_svi_calibration

Evidence considered

• REVEL score = 0.095 for NM_001127208.2:c.2119G>A (p.Ala707Thr) meets the ClinGen SVI-calibrated BP4_Moderate threshold (<=0.183) per Pejaver et al. 2022 (PMID 36413997), supporting a benign in-silico prediction at moderate strength.
• SpliceAI shows no meaningful splice impact (max delta score = 0.002; all individual DS scores <=0.002), which is consistent with the missense-only interpretation and does not add a separate splice-based benign code alongside the REVEL-based BP4 call.
• BayesDel score (-0.507189) was retrieved but not used to strengthen or independently support BP4 because no verified published threshold/PMID for BayesDel calibration is available to this pipeline.

Sources

Reasoning

PM1 requires the variant to fall in a well-established mutational hotspot or critical, functionally important domain without benign variation. Cancerhotspots.org query for TET2 A707 returned no result (search_status=no_result), and COSMIC returned no somatic recurrence at this position, arguing against a statistical hotspot. No UniProt/InterPro/Pfam domain-boundary annotation for TET2 was retrieved in this case bundle to confirm or exclude residue 707 from the catalytic (DSBH/Cys-rich, approx. residues 1134-1936) or CXXC domains of TET2; residue 707 lies in the large, poorly conserved central region of the 2002-aa protein outside those established catalytic elements based on general TET2 domain architecture. Given the explicit absence of hotspot/somatic recurrence signal and no domain evidence supporting residue 707 as functionally critical, PM1 is not met.

Rule

generic_ACMG_2015_PM1

Evidence considered

• cancerhotspots.org query 'TET2 A707' returned search_status=no_result / found=false with evidence_sentence 'This variant does not lie in a statistically significant hotspot.'
• COSMIC search for TET2 c.2119G>A returned found=false with evidence_sentence 'This variant has not previously been reported in somatic cancers (COSMIC).'
• OncoKB query for TET2 A707T returned classification 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence, consistent with no established hotspot/functional-domain signal at this residue.

Still missing

• No UniProt/InterPro domain-boundary data for TET2 was retrieved in this case; a formal domain-mapping check for residue 707 (relative to the CXXC and DSBH/Cys-rich catalytic domains) is recommended for full confidence.

Reasoning

PP2 requires a gene with a low rate of benign missense variation where missense variants are a common/established mechanism of disease. The germline disease-context literature review for TET2 captured in this case (pvs1_gene_context.json) specifically supports loss-of-function (nonsense/frameshift-type) as the germline disease mechanism ('lof_mechanism_supported': true; 'mechanism_rationale': targeted literature review identified TET2 loss-of-function as the germline disease mechanism), based on reports of germline TET2 LOF variants causing an ALPS-like phenotype/hematologic malignancy predisposition. No source in this bundle establishes missense variation itself as a recurrent, common disease mechanism for TET2 (no missense-constraint metric or dominant-negative/gain-of-function missense literature was retrieved), so PP2 is not met.

Rule

generic_ACMG_2015_PP2

Evidence considered

• pvs1_gene_context.json states lof_mechanism_supported=true and mechanism_rationale identifying TET2 loss-of-function (not missense) as the supported germline disease mechanism, based on targeted literature review of germline TET2 disease reports.

Still missing

• No gene-level missense constraint metric (e.g., missense Z-score/observed-expected ratio) was retrieved in this case to further quantify tolerance to benign missense variation.

Sources

Reasoning

No governing VCEP/CSPEC was found for TET2 (case_summary.json framework_mode='generic_acmg', cspec.found=false), so generic ACMG/AMP computational-evidence rules apply. NM_001127208.2:c.2119G>A (p.Ala707Thr) is a missense substitution. REVEL score = 0.095, well below the ClinGen SVI-calibrated REVEL supporting threshold for pathogenic evidence (>=0.644) established in the Pejaver et al. 2022 recalibration (PMID 36413997); PP3 is therefore not met on the missense computational path. SpliceAI predicts no splice impact for this substitution (max delta score = 0.002, far below any SpliceAI PP3 threshold), so the splice-impact path also does not support PP3. BayesDel is available (score -0.507189) but is not used because no verified published threshold/publication for BayesDel calibration is available to this evaluation, per pipeline policy treating uncited BayesDel cutoffs as not_available.

Rule

generic_acmg_2015

Evidence considered

• REVEL score = 0.095 for NM_001127208.2:c.2119G>A (p.Ala707Thr), below the ClinGen SVI-calibrated PP3 supporting threshold of >=0.644 for REVEL (Pejaver et al. 2022, PMID 36413997).
• SpliceAI predicts no significant splice impact for this variant (DS_AG=0.00, DS_AL=0.00, DS_DG=0.00, DS_DL=0.002; max delta score = 0.002), well below any threshold used to invoke PP3 on the splice-impact path.
• BayesDel score (-0.507189) was retrieved but excluded from PP3 consideration because no verified published threshold/PMID for BayesDel calibration could be cited; per pipeline policy this predictor is treated as not_available for calibrated computational evidence.

Sources

Reasoning

BA1 is not met. The variant is far below the generic population-frequency threshold for stand-alone benign evidence (>1%): gnomAD v4.1 reports total AF 6.195917386115941e-07 (1/1,613,966 alleles), with the highest reported population AF 8.474418273557612e-07 in European (non-Finnish) samples.

Rule

Generic population-frequency rule: BA1 requires an allele frequency greater than 1% in a relevant reference population; use the highest reliable population frequency.

Evidence considered

• gnomAD v4.1 reports 1 alternate allele among 1,613,966 total alleles (AF 6.195917386115941e-07; 0.000061959%); the highest listed subpopulation frequency is European non-Finnish AF 8.474418273557612e-07 (1/1,180,022 alleles).
• The observed frequency is orders of magnitude below the generic BA1 threshold of >1%.
• No applicable TET2 VCEP or gene-specific framework was retrieved; generic ACMG/AMP fallback was therefore used.

Sources

Reasoning

BS1 is not met. The variant frequency is not greater than the disease-mechanism-compatible maximum expected frequency threshold (>0.3% under the generic non-VCEP operating threshold); the highest observed gnomAD v4.1 population AF is 8.474418273557612e-07.

Rule

Generic population-frequency rule: BS1 requires a frequency higher than the maximum credible frequency for the associated disease; absent a gene-specific threshold, the generic operating threshold is >0.3% using the highest reliable population frequency.

Evidence considered

• gnomAD v4.1 reports total AF 6.195917386115941e-07 from 1/1,613,966 alleles and highest listed subpopulation AF 8.474418273557612e-07 in European non-Finnish samples.
• The observed frequency is far below the generic BS1 threshold of >0.3%.
• Because no TET2-specific prevalence/penetrance model or VCEP rule was retrieved, a disease-specific maximum credible frequency could not be calculated; this limitation does not affect the conclusion that the observed frequency does not support BS1.

Still missing

• No TET2-specific disease prevalence, penetrance, or maximum credible allele-frequency model was available to derive a gene/disease-specific BS1 threshold.

Sources

Reasoning

BS2 is not met. gnomAD v4.1 reports zero homozygotes for the variant overall and in the highest-frequency European non-Finnish population; gnomAD v2.1 and gnomAD-Canada v1.0 report the variant as absent. No unaffected adult homozygote or other healthy-control observation was identified.

Rule

Generic BS2 rule: apply only when the variant is observed in healthy adults, typically as homozygotes/hemizygotes for a recessive condition or in multiple unaffected individuals when that observation contradicts the expected disease model.

Evidence considered

• gnomAD v4.1 reports total homozygotes = 0 and European non-Finnish homozygotes = 0; the variant is observed only as a single allele in the reported dataset.
• The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
• No source in the case bundle reports an unaffected adult homozygote, multiple unaffected heterozygotes with appropriate phenotype assessment, or an equivalent healthy-control observation.

Still missing

• Population databases do not establish complete adult health status or penetrance for every carrier, so they cannot independently exclude undiagnosed heterozygous disease or age-dependent effects.

Sources

Reasoning

PS1 requires that the same amino acid change (p.Ala707Thr) has already been established as pathogenic via a different nucleotide substitution. No CSPEC/VCEP exists for TET2 (cspec.found=false, gene_vcep_dir=null), so generic ACMG applies. The consolidated bundle contains no comparator-variant search results (ClinVar or literature) for alternate codon changes producing the identical p.Ala707Thr substitution; the only ClinVar record present is for this exact variant (VCV004182982, Uncertain significance, 1 submitter), which cannot be used as its own PS1 comparator.

Rule

generic_ACMG_2015_PS1

Evidence considered

• ClinVar record for NM_001127208.2:c.2119G>A (VCV004182982) itself shows Uncertain significance with 1 submitter and is not a valid same-codon comparator for PS1.
• No other source in the case bundle (prefetch, evidence, literature_pass, vcep_materials) reports an independent pathogenic variant producing the same p.Ala707Thr change via a different nucleotide substitution.

Still missing

• No dedicated PS1 same-amino-acid-change comparator search was performed or captured in the case bundle; a targeted ClinVar/literature search for other codon changes yielding p.Ala707Thr is needed before this criterion can be finalized.

Sources

Reasoning

No proband-level de novo observation or confirmed maternity and paternity is documented in the case-evidence bundle. The available records contain variant normalization and population/database results but no parental testing, trio data, or de novo event.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no confirmed parental origin; strength depends on confirmation of maternity/paternity and phenotype consistency.

Evidence considered

• The case-evidence bundle reports no PMIDs, no VCEP specification, and no family or parental-testing data.
• ClinVar contains one single-submitter uncertain-significance record for the variant, but it does not provide usable criterion-level de novo evidence.

Still missing

• Proband phenotype and case-level report
• Parental genotypes with confirmed maternity and paternity
• Validated de novo status and assessment of parental mosaicism

Reasoning

No functional/biochemical assay data addressing TET2 p.(Ala707Thr) were identified in the assembled evidence. No ClinGen VCEP specification exists for TET2 (final_classification_framework indicates generic_acmg_fallback, official_clingen=false), so no gene-specific PS3 assay validation rules apply. literature_pass.json reports total_pmids=0 with no PMIDs identified across evidence sources, and no publications were retrieved into fulltext_map.json for this case. OncoKB was queried but found no variant-specific reviewed functional evidence (is_variant_specific=false, not_reviewed=true), only generic gene-level context that TET2 is a DNA demethylase/tumor suppressor. No hydroxymethylation, dioxygenase activity, or other validated functional assay results for this specific variant were located.

Still missing

• No published functional/biochemical assay (e.g., 5hmC production, catalytic dioxygenase activity) for TET2 p.(Ala707Thr) was located in the assembled evidence or literature search.
• No ClinGen TET2 VCEP specification available to define validated assay types or evidence strength calibration for this gene.
• literature_pass.json returned zero PMIDs; a targeted literature search for TET2 functional characterization of this specific variant has not been completed within this case.

Reasoning

No case-control enrichment data, affected/unaffected cohort counts, or variant-specific disease prevalence evidence were available for NM_001127208.2:c.2119G>A (TET2 p.Ala707Thr). PS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires statistically significant enrichment in affected individuals compared with controls; no applicable TET2-specific framework was retrieved.

Evidence considered

• The consolidated evidence bundle reports no literature PMIDs and contains no case-control or cohort prevalence analysis for the exact variant.

Still missing

• Variant-specific case and control counts or a validated case-control enrichment analysis are unavailable.
• No phenotype-linked cohort evidence for this exact variant was identified.

Reasoning

No affected-proband observations, second pathogenic/likely pathogenic variant, phase information, or inheritance data are documented for NM_001127208.2:c.2119G>A (p.Ala707Thr). Therefore PM3 cannot be assessed.

Rule

Generic ACMG/AMP PM3: pathogenic variants identified in trans with the variant under assessment support a recessive disease mechanism; evaluation requires documented affected-proband observations and reliable phase/inheritance evidence.

Evidence considered

• The consolidated case-evidence bundle contains no family, proband, genotype-phase, compound-heterozygosity, or inheritance observations for this variant.
• The applicable framework is generic ACMG/AMP because no TET2-specific VCEP/CSPEC specification was retrieved.

Still missing

• Affected-proband case data are absent.
• No pathogenic or likely pathogenic allele in the same proband is documented.
• No cis/trans phase or inheritance information is available.

Reasoning

PM5 requires a different missense change at the same residue (position 707) previously established as pathogenic. The case's own PM5 candidate-harvesting step (pm5_candidates.json) explicitly declined to run: pm5_mode='unknown', eligible_for_classic_pm5_search=false, total_candidates_seen=0, with recommendation level 'not_applicable' pending manual review ('Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting'). No other source in the bundle supplies same-residue comparator variant data, so PM5 cannot be adjudicated from the evidence available in this case.

Rule

generic_ACMG_2015_PM5

Evidence considered

• pm5_candidates.json for this case reports pm5_mode='unknown', eligible_for_classic_pm5_search=false, and zero same-residue candidates collected, recommending manual review rather than automatic PM5 application.

Still missing

• A manual ClinVar/literature search for other pathogenic/likely pathogenic missense variants at TET2 codon 707 (e.g. p.Ala707Val, p.Ala707Gly, p.Ala707Pro, p.Ala707Ser) is required; the automated pm5_candidates harvesting step was skipped for this case.

Sources

Reasoning

No suspected de novo occurrence without confirmed parental relationships is reported for this variant. The case-evidence bundle contains no proband report, parental testing, or literature case describing the variant.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence when maternity and paternity are not confirmed; apply only when a compatible affected individual and credible suspected de novo evidence are documented.

Evidence considered

• The literature pass found no PMIDs and the full-text map is empty.
• The case summary provides no family history, meioses, or parental-genotype observations.

Still missing

• A documented patient with the exact variant and a compatible phenotype
• Evidence that the variant was absent from tested parents or otherwise suspected to be de novo
• Available parental relationship and mosaicism information

Reasoning

No affected relatives, unaffected relatives, informative meioses, or cosegregation observations are documented. Therefore, no segregation evidence is available to support PP1 at supporting, moderate, or strong strength.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members; strength is calibrated by the number and informativeness of meioses.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree, family-genotype, segregation, or meiosis data.
• No publication was identified that reports the exact variant in a segregating family.

Still missing

• Family pedigree and phenotypic status of relatives
• Genotypes of informative affected and unaffected relatives
• Number of informative meioses and segregation concordance

Reasoning

No patient phenotype, clinical diagnostic information, or syndrome-specific phenotype description was provided for the case. The available TET2 and variant records do not establish a highly specific phenotype in this individual, so PP4 cannot be assessed.

Rule

Generic ACMG/AMP PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single-gene etiology; phenotype specificity is not documented.

Evidence considered

• The consolidated evidence bundle contains no case phenotype description and reports no literature PMIDs for the exact variant.

Still missing

• Patient phenotype and diagnostic features are not available.
• No exact-variant report linking a specific phenotype to this variant was identified.

Reasoning

No functional/biochemical assay data addressing TET2 p.(Ala707Thr) were identified in the assembled evidence, so no basis exists to conclude the variant has normal (wild-type-like) function. No ClinGen VCEP specification exists for TET2 to define validated assay types or BS3 calibration. literature_pass.json reports zero PMIDs identified, and OncoKB found no variant-specific reviewed functional evidence (is_variant_specific=false, not_reviewed=true).

Still missing

• No published functional assay showing normal/wild-type activity for TET2 p.(Ala707Thr) was located in the assembled evidence or literature search.
• No ClinGen TET2 VCEP specification available to define validated assay types or evidence strength calibration for this gene.
• literature_pass.json returned zero PMIDs; a targeted literature search for TET2 functional characterization of this specific variant has not been completed within this case.

Reasoning

No unaffected relatives who were tested for the variant are documented. Absence of segregation or non-segregation evidence cannot be established from the available case data, so BS4 cannot be applied.

Rule

Generic ACMG/AMP BS4: lack of segregation in an affected family, or presence of the variant in sufficiently informative unaffected relatives, when phenotype assessment and penetrance are adequate.

Evidence considered

• The case-evidence bundle reports no relatives, parental testing, family pedigree, or non-segregation observations.
• The available database records do not contain family-level evidence relevant to BS4.

Still missing

• Phenotypically unaffected relatives with reliable clinical assessment
• Genotype results for those relatives
• Adequate age, penetrance, and phenotype information to interpret non-segregation

Reasoning

No case-level observation documents NM_001127208.2:c.2119G>A (p.Ala707Thr) in cis or trans with a pathogenic or likely pathogenic variant, and no phase or inheritance data are available. Therefore BP2 cannot be assessed.

Rule

Generic ACMG/AMP BP2: the variant is observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant for any inheritance pattern; reliable phase and relevant clinical context are required.

Evidence considered

• The consolidated case-evidence bundle contains no family, proband, co-occurring pathogenic-variant, genotype-phase, or inheritance observations relevant to BP2.
• The applicable framework is generic ACMG/AMP because no TET2-specific VCEP/CSPEC specification was retrieved.

Still missing

• No affected or unaffected proband genotype data are documented for allelic comparison.
• No pathogenic or likely pathogenic variant paired with the target variant is documented.
• No cis/trans phase or inheritance information is available.

Reasoning

No information was available showing that the patient has an alternative molecular diagnosis explaining the phenotype while this variant is present. BP5 therefore cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires an alternate molecular basis that explains the phenotype; no such case evidence is available.

Evidence considered

• The consolidated evidence bundle contains no case-level alternative diagnosis or competing pathogenic variant evidence.

Still missing

• No patient-level molecular findings or alternative pathogenic variant were provided.
• No phenotype and segregation information is available to determine whether another diagnosis explains the case.