ARID1A c.2297A>T, p.(Gln766Leu)

Reasoning

NM_006015.5:c.2297A>T (ARID1A p.Gln766Leu) is recorded as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. This supports the generic ACMG/AMP PM2 rare/absent-in-population-databases criterion at supporting strength. The result is limited by the absence of allele-number and coverage details in the bundle and by the lack of an ARID1A-specific VCEP specification.

Rule

Generic ACMG/AMP PM2: absent from controls in population databases, or extremely low frequency if recessive; applied at supporting strength because no applicable ARID1A-specific VCEP rule was retrieved.

Evidence considered

• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD v2.1.
• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD v4.1.
• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD-Canada v1.0.
• Under the generic ACMG/AMP framework, absence from population databases supports PM2 at supporting strength when no applicable gene-specific rule supersedes it.

Still missing

• No allele-number, coverage, ancestry-stratified count, or quality details were available beyond the recorded absent-result status.
• No ARID1A-specific VCEP population rule was retrieved.

Sources

Reasoning

No official CSPEC/VCEP framework is available for ARID1A; generic calibrated computational thresholds apply. REVEL score is 0.256 for NM_006015.5:c.2297A>T (p.Gln766Leu), which meets the ClinGen SVI-recommended REVEL BP4 supporting threshold (<=0.290 per Pejaver et al. 2022, PMID:36413997), indicating a REVEL-predicted benign/tolerated effect. This is corroborated by SpliceAI, which predicts no significant splice impact at this position (max delta score = 0.032, all four delta scores <0.1), consistent with no splice-disruptive mechanism. Both lines of evidence point the same direction (benign/no impact) without conflict, so BP4 is applied at supporting strength using the REVEL calibrated threshold as the primary driver, with SpliceAI as corroborating evidence of no splice disruption (not separately counted).

Rule

generic_acmg_pp3_bp4_revel_spliceai

Evidence considered

• REVEL score 0.256 for NM_006015.5:c.2297A>T (p.Gln766Leu), local REVEL v1.3 lookup.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) sets BP4 supporting threshold at REVEL <=0.290; 0.256 satisfies this, supporting BP4 at supporting strength.
• SpliceAI Lookup: max delta score = 0.032 (DS_AG 0.001, DS_AL 0.017, DS_DG 0.0, DS_DL 0.032), no significant predicted splice impact, corroborating a benign computational prediction (not independently counted toward BP4 strength beyond REVEL).
• BayesDel score (-0.249382) exists in source_registry but is excluded here as insufficiently calibrated for this pipeline (no verified published threshold publication).

Sources

Reasoning

No official CSPEC/VCEP framework is available for ARID1A (framework_mode=generic_acmg; cspec.found=false), so generic calibrated computational thresholds apply. NM_006015.5:c.2297A>T is a missense variant (p.Gln766Leu) at a non-canonical splice position (canonical_splice_consensus=false). REVEL score is 0.256, which falls below the ClinGen SVI-recommended REVEL supporting threshold for pathogenic prediction (>=0.644 per Pejaver et al. 2022, PMID:36413997), so REVEL does not support PP3. SpliceAI max delta score is 0.032 (DS_AG 0.001, DS_AL 0.017, DS_DG 0.0, DS_DL 0.032), far below any splice-impact threshold, so no splice-disruption evidence supports PP3 either. BayesDel score (-0.249382) is available locally but is excluded from this determination because this pipeline has no verified published calibration/threshold publication for BayesDel; it is treated as not_available per policy rather than as supporting or refuting evidence.

Rule

generic_acmg_pp3_bp4_revel_spliceai

Evidence considered

• REVEL score 0.256 for NM_006015.5:c.2297A>T (p.Gln766Leu), computed via local REVEL v1.3 lookup.
• ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997) sets PP3 supporting threshold at REVEL >=0.644; 0.256 is well below this, so PP3 is not triggered.
• SpliceAI Lookup result: max delta score = 0.032 (DS_AG 0.001, DS_AL 0.017, DS_DG 0.0, DS_DL 0.032), indicating no significant predicted splice impact, so no splicing-based PP3 applies.
• No governing ClinGen VCEP/gene-specific framework (e.g. PP3/BP4 lookup spreadsheet) was found for ARID1A in vcep_materials.json; generic ACMG/AMP fallback used.

Still missing

• No BayesDel calibrated threshold publication is available to this pipeline; BayesDel score not usable for PP3/BP4 despite being locally computed.

Sources

Reasoning

PP5 is not met because the exact variant NM_006015.5:c.2297A>T is reported as absent from ClinVar, with no ClinVar variation ID, classification, review status, or expert-panel assertion. No expert-panel Pathogenic or Likely pathogenic classification is available.

Rule

PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; absent or non-expert ClinVar evidence does not satisfy PP5.

Evidence considered

• ClinVar search for the exact transcript variant NM_006015.5:c.2297A>T returned no result; the case bundle states: 'This variant is absent from ClinVar.'
• The ClinVar submission audit reports variation_id null, classification empty, review_status empty, submitter_count 0, and expert_panels empty.
• Under the requested rule, ordinary submissions, aggregate labels, and non-expert assertions cannot trigger PP5; no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion exists here.

Sources

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Therefore, there is no observed population allele frequency approaching the generic ACMG/AMP BA1 threshold (>5%).

Rule

Generic ACMG/AMP BA1: stand-alone benign evidence requires an allele frequency greater than 5% in a population database; no applicable ARID1A-specific VCEP rule was retrieved.

Evidence considered

• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD v2.1.
• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD v4.1.
• The case evidence records NM_006015.5:c.2297A>T as absent from gnomAD-Canada v1.0.
• No population frequency is available that could meet the generic ACMG/AMP BA1 threshold of greater than 5%.

Still missing

• No independently verified allele-count or allele-number table was available in the case bundle; the adjudication relies on the recorded absent-result status from each population database.

Sources

Reasoning

The variant is absent from the available gnomAD datasets, so no allele frequency above the disease-specific expected maximum has been demonstrated. Disease prevalence, penetrance, and an ARID1A-specific maximum credible population frequency were not provided, but the available population observations do not support BS1.

Rule

Generic ACMG/AMP BS1: allele frequency is greater than expected for the disorder; an applicable ARID1A-specific population-frequency rule was not retrieved.

Evidence considered

• The case evidence records the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
• Because no nonzero population frequency is reported, the available data do not exceed any disease-specific maximum credible frequency and do not establish BS1.

Still missing

• No disease-specific maximum credible allele frequency was available.
• No disease prevalence or penetrance estimates were available for an independent threshold calculation.
• No allele-count or allele-number details were available beyond the recorded absent-result status.

Sources

Reasoning

BP6 is not met because the exact variant NM_006015.5:c.2297A>T is absent from ClinVar and has no expert-panel Benign or Likely benign classification. No qualifying ClinVar expert-panel assertion is available.

Rule

BP6 applies only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; absent or non-expert ClinVar evidence does not satisfy BP6.

Evidence considered

• ClinVar search for the exact transcript variant NM_006015.5:c.2297A>T returned no result; the case bundle states: 'This variant is absent from ClinVar.'
• The ClinVar submission audit reports variation_id null, classification empty, review_status empty, submitter_count 0, and expert_panels empty.
• Under the requested rule, ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6; no exact-variant ClinVar expert-panel Benign/Likely benign assertion exists here.

Sources

Reasoning

PS1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No proband-specific de novo evidence is available in the case-evidence bundle. The bundle contains no parental testing results, maternity/paternity confirmation, or documented unaffected parents for NM_006015.5:c.2297A>T (ARID1A p.Gln766Leu), so PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with confirmed maternity and paternity; insufficient case-level evidence means not assessed.

Evidence considered

• The consolidated case-evidence bundle reports no family, parental-testing, or de novo observations for this variant; its literature_pass section reports total_pmids = 0 and no criterion-specific literature evidence.
• Absence from gnomAD and ClinVar does not establish de novo occurrence and was not used as PS2 evidence.

Still missing

• Proband phenotype and clinical indication are not documented in the case-evidence bundle.
• No parental genotypes or validated maternity/paternity information are provided.
• No evidence establishes that the variant is de novo rather than inherited or present in parental mosaicism.

Reasoning

No ClinGen VCEP/CSPEC functional criteria specification exists for ARID1A (cspec.found=false; final_classification_framework.found=false, generic_acmg_fallback). No published functional/biochemical assay data (e.g., reporter assay, complementation, transcriptional activity, chromatin-remodeling activity) for NM_006015.5:c.2297A>T (p.Gln766Leu) was identified in the case bundle. OncoKB reports no variant-specific reviewed functional evidence ('Unknown Oncogenic Effect'), and the literature search returned zero PMIDs indexed for functional criteria (literature_packet.criteria_index empty, total_pmids=0). No validated assay system, controls, or replicate data are available to assess.

Evidence considered

• case_summary.json vcep_materials.final_classification_framework.found = false; framework source = generic_acmg_fallback; no CSPEC/VCEP functional (PS3/BS3) assay framework available for ARID1A.
• OncoKB evidence_sentence: 'OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up.'
• literature_packet.total_pmids = 0 and criteria_index is empty, indicating no literature-derived functional assay data was captured for this variant.

Still missing

• No validated functional assay (e.g., transactivation, chromatin remodeling, complementation) for this specific variant was located in the case materials.
• No VCEP/CSPEC PS3 assay-validation framework exists for ARID1A to define approved assays or strength calibration.
• OncoKB functional annotation is gene-level only, not variant-specific reviewed evidence.

Reasoning

No affected-case series, case-control comparison, enrichment statistic, or variant-specific disease cohort was provided for NM_006015.5:c.2297A>T. The available bundle reports no variant-specific literature records and therefore does not support PS4.

Rule

Generic ACMG/AMP PS4: use statistically significant enrichment of the variant in affected individuals compared with appropriate controls; no applicable ARID1A-specific VCEP specification was retrieved.

Evidence considered

• The case-evidence bundle identifies NM_006015.5:c.2297A>T (ARID1A, p.Gln766Leu) but reports no PMIDs and no case-control or clinical case-series evidence.
• PS4 requires reliable affected-case enrichment relative to controls; absence of such data is insufficient to call PS4 met or not_met.

Still missing

• Affected-case count and ascertainment data for this exact variant are unavailable.
• A suitable control cohort and statistical enrichment estimate are unavailable.
• No variant-specific publication or case series was identified in the evidence bundle.

Reasoning

PM1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No applicable ARID1A-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP PM3 concept applies. The case-evidence bundle contains no affected-proband observations, confirmed biallelic disease, phase information, or a pathogenic/likely pathogenic variant documented in trans with NM_006015.5:c.2297A>T. PM3 cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP PM3: apply only when the variant is observed in trans with a pathogenic or likely pathogenic variant in an affected individual or when equivalent biallelic evidence supports the recessive disease mechanism; no applicable ARID1A-specific modification was retrieved.

Evidence considered

• The bundle identifies ARID1A as lacking a retrieved CSPEC/VCEP framework and specifies generic ACMG/AMP fallback.
• The available case evidence reports no literature PMIDs, no ClinVar record, and no family, proband, phase, cis/trans, or inheritance observations relevant to PM3.

Still missing

• Affected-proband observations are not provided.
• No second pathogenic or likely pathogenic variant is documented.
• Phase or inheritance information is not provided.
• No evidence establishes biallelic disease for this variant.

Sources

Reasoning

PM5 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No probable de novo evidence is available in the case-evidence bundle. There are no parental testing results, maternity/paternity details, or proband phenotype data to support a de novo event without full confirmation, so PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6 may support a probable de novo variant when parental confirmation is incomplete; no qualifying case-level observation is available here, so not assessed.

Evidence considered

• The consolidated case-evidence bundle contains no parental, trio, family, or de novo findings for NM_006015.5:c.2297A>T.
• Population absence is not evidence of probable de novo occurrence and was not used for PM6.

Still missing

• No documented de novo observation in the proband.
• No parental genotypes or maternity/paternity information are provided.
• No clinical phenotype information is provided to establish that the proband is affected.

Reasoning

No segregation data are available for the case. The evidence bundle does not identify affected or unaffected relatives, informative meioses, variant genotypes in relatives, or phenotype concordance, so PP1 cannot be assessed at any strength.

Rule

Generic ACMG/AMP PP1 requires cosegregation with disease in affected family members, with strength dependent on informative meioses and the applicable framework; no segregation observations are available, so not assessed.

Evidence considered

• The consolidated case-evidence bundle contains no family segregation observations and no criterion-specific literature evidence.
• The variant's absence from population and clinical databases does not provide segregation evidence and was not used for PP1.

Still missing

• No family pedigree or number of informative meioses is provided.
• No segregation genotypes for affected or unaffected relatives are provided.
• No phenotype consistency information is provided for relatives.

Reasoning

PP2 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

The bundle contains no patient phenotype description and no disease-specific phenotype comparison for this variant. ARID1A gene-level context alone is not sufficient to establish a highly specific phenotype for PP4.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or highly specific disease features must be highly specific for a disease with a single-gene etiology; no applicable ARID1A-specific VCEP specification was retrieved.

Evidence considered

• The case summary identifies ARID1A p.Gln766Leu but provides no clinical presentation, phenotype terms, or disease-specific diagnostic findings.
• A gene-level statement that ARID1A is associated with developmental or cancer-related conditions does not demonstrate a highly specific phenotype in this individual.

Still missing

• Individual clinical phenotype and diagnostic features are unavailable.
• The relevant ARID1A-associated disease phenotype and its specificity to the observed presentation are not documented for this case.
• No phenotype-matched case report or cohort was identified.

Reasoning

No healthy adult homozygote or hemizygote observation, and no appropriately documented unaffected individual observation, was identified in the supplied population evidence. Database absence cannot by itself establish the BS2 observation requirement.

Rule

Generic ACMG/AMP BS2: observed in a healthy adult individual for a fully penetrant dominant disorder, or in healthy adults in the relevant zygosity for recessive/X-linked disorders; no applicable ARID1A-specific VCEP rule was retrieved.

Evidence considered

• The supplied gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada records report the variant as absent rather than documenting healthy adult carriers or homozygotes.
• The absence result does not provide the healthy-adult homozygote/hemizygote evidence required for BS2.

Still missing

• No individual-level healthy adult genotype observations were available.
• No homozygote or hemizygote counts were available from the population datasets.
• No phenotype-confirmed unaffected cohort was available for assessment.

Sources

Reasoning

Same evidentiary gap as PS3: no ClinGen VCEP/CSPEC framework exists for ARID1A, and no published functional assay data (variant-specific, with appropriate wild-type/negative controls) demonstrating normal/benign functional effect for NM_006015.5:c.2297A>T (p.Gln766Leu) was found in the case bundle. No basis exists to assess a benign functional signal.

Evidence considered

• case_summary.json vcep_materials.final_classification_framework.found = false; no CSPEC/VCEP functional assay framework for ARID1A.
• literature_packet.total_pmids = 0; no functional studies captured referencing this variant.

Still missing

• No functional assay data of any kind (pathogenic or benign-supporting) for this variant was located.
• No VCEP/CSPEC PS3/BS3 assay-validation framework exists for ARID1A.

Reasoning

No non-segregation evidence is available. The case-evidence bundle contains no genotyped unaffected affected relatives, no informative relatives who lack the variant, and no phenotype/family data suitable for evaluating BS4.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected family members when the phenotype is disease-specific; absent family and genotype data make this criterion not assessed.

Evidence considered

• The consolidated case-evidence bundle contains no family non-segregation observations for NM_006015.5:c.2297A>T.
• No unaffected-relative or affected-relative testing results are available; therefore no evidence was used for BS4.

Still missing

• No pedigree or family phenotypes are provided.
• No genotypes from affected relatives are provided to demonstrate absence of the variant.
• No assessment of phenotype specificity or alternative explanations is provided.

Reasoning

BP1 could not be assessed because its agent did not produce valid output.

Still missing

• attempt 1: evidence_refs must contain only source_registry keys
• attempt 2: evidence_refs must contain only source_registry keys
• attempt 3: evidence_refs must contain only source_registry keys

Reasoning

No applicable ARID1A-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP BP2 concept applies. The case-evidence bundle contains no affected or unaffected family observations, no phase information, and no documentation that NM_006015.5:c.2297A>T occurs in cis with a pathogenic variant or in trans with a benign variant. BP2 cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP BP2: apply when the variant is observed in trans with a pathogenic variant or in cis with a pathogenic variant in a recessive disorder, as applicable to the disease model; no applicable ARID1A-specific modification was retrieved.

Evidence considered

• The bundle identifies ARID1A as lacking a retrieved CSPEC/VCEP framework and specifies generic ACMG/AMP fallback.
• The available case evidence contains no family, phase, cis/trans, or inheritance observations relevant to BP2.

Still missing

• No family or proband segregation observations are provided.
• No pathogenic variant in cis or benign variant in trans is documented.
• Phase information is not provided.
• No inheritance-mode evidence is available.

Sources

Reasoning

No evidence was provided that the patient's phenotype is explained by an established alternative molecular etiology, and no appropriate alternative diagnosis or molecular finding is documented. BP5 therefore cannot be assessed from this bundle.

Rule

Generic ACMG/AMP BP5: a pathogenic variant in an alternative gene or an established alternative molecular etiology explains the patient's phenotype; no applicable ARID1A-specific VCEP specification was retrieved.

Evidence considered

• The case bundle contains no clinical phenotype, family diagnostic workup, or alternative pathogenic molecular finding for the patient.
• Gene-level cancer and ARID1A context does not establish an alternative molecular etiology for this individual and cannot be used alone for BP5.

Still missing

• Patient phenotype and diagnostic workup are unavailable.
• No confirmed alternative molecular etiology is documented.
• No evidence links the observed phenotype to another pathogenic variant or diagnosis.