RAD51B c.82C>G, p.(Gln28Glu)

Reasoning

The variant is absent from gnomAD-Canada and is present only at an extremely low frequency in gnomAD v2.1 and v4.1. The maximum observed subgroup frequency in gnomAD v4.1 is 0.01653%, and the overall frequency is 0.000435%, both below the generic PM2 threshold of <0.1%; no homozygotes are observed.

Rule

Generic ACMG/AMP population threshold: PM2 supporting is met when the variant is absent or has MAF <0.1% in appropriate population databases; no applicable RAD51B-specific specification was available.

Evidence considered

• gnomAD v4.1: 7/1,609,138 alleles, total AF 4.35016e-06 (0.000435%), no homozygotes; highest subgroup AF 0.000165344 (0.01653%) in the Middle Eastern subgroup.
• gnomAD v2.1: 2/248,786 alleles, total AF 8.03904e-06 (0.000804%), no homozygotes; highest reported subgroup AF 1.76929e-05 (0.00177%) in the European non-Finnish subgroup.
• gnomAD-Canada v1.0 reports the variant as absent.
• Generic population rule applied because no RAD51B-specific VCEP/CSPEC framework was retrieved: PM2 supporting is met for absent or extremely rare variants with MAF <0.1%.

Sources

Reasoning

Both calibrated computational predictors available for this variant point toward a benign/no-effect prediction with no conflicting pathogenic signal. SpliceAI's max delta score of 0.056 is well below the 0.2 splice-altering threshold, indicating no predicted disruption of splicing. REVEL, the missense predictor with an available named-publication threshold, scores 0.071, a low value consistent with a benign missense effect under the ClinGen SVI-recommended REVEL calibration. No VCEP-specific PP3/BP4 lookup table exists for RAD51B to override this generic assessment. BP4 is applied once at supporting strength, combining agreement across the splice-impact and missense in silico paths without double counting.

Rule

generic_acmg_pp3_bp4_computational_evidence

Evidence considered

• SpliceAI Lookup (NM_133509.4:c.82C>G, hg37): max delta score = 0.056, indicating no significant predicted splice impact.
• REVEL local predictor lookup at 14:67823625 C>G: score = 0.071, below benign-supporting thresholds per the ClinGen SVI-recommended REVEL calibration (PMID 36413997).

Still missing

• No ClinGen VCEP specification exists for RAD51B; generic ACMG in silico thresholds were applied.
• BayesDel score (-0.414292) is present but excluded because no verified published threshold/PMID for BayesDel is available to this pipeline.

Sources

Reasoning

No pathogenic in silico signal is present on either the splicing or missense path for this variant. RAD51B has no ClinGen VCEP specification and no gene-specific PP3/BP4 lookup material was found in this case bundle, so generic ACMG/AMP calibrated-tool guidance applies. SpliceAI predicts no significant splice impact (max delta score = 0.056, well below the 0.2 threshold used for splice-altering prediction), and REVEL, the only missense predictor with a named published calibration available to this pipeline, gives a low score of 0.071 (well below pathogenic-supporting thresholds), consistent with a benign missense prediction rather than a deleterious one. Since neither path predicts damaging/splice-altering effect, PP3 is not met.

Rule

generic_acmg_pp3_bp4_computational_evidence

Evidence considered

• SpliceAI Lookup (NM_133509.4:c.82C>G, hg37): max delta score = 0.056 (DS_AG=0.005, DS_AL=0.001, DS_DG=0.056, DS_DL=0.004), interpreted as 'no significant splice impact predicted.'
• REVEL local predictor lookup at 14:67823625 C>G: score = 0.071, a low (benign-leaning) score using the ClinGen SVI-recommended REVEL calibration (PMID 36413997).

Still missing

• No ClinGen VCEP specification exists for RAD51B; generic ACMG in silico thresholds were applied.
• A BayesDel score is present in source data (-0.414292) but is excluded from this assessment because no verified published threshold/PMID for BayesDel is available to this pipeline.

Sources

Reasoning

PP5 is not met. The exact variant NM_133509.4:c.82C>G is reported as absent from ClinVar, with no exact-variant expert-panel Pathogenic or Likely pathogenic classification. No other source can trigger PP5 under the specified rule.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant searching found no result for NM_133509.4:c.82C>G; therefore there is no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertion to support PP5.

Sources

Reasoning

The variant does not meet the generic BA1 population-frequency threshold of >1%. gnomAD v4.1 reports a total allele frequency of 4.35016e-06 (0.000435%) and a maximum observed population frequency of 0.000165344 (0.01653%); gnomAD v2.1 reports a total allele frequency of 8.03904e-06 (0.000804%).

Rule

Generic ACMG/AMP population threshold: BA1 is met only when allele frequency is >1%; no applicable RAD51B-specific specification was available.

Evidence considered

• gnomAD v4.1: 7/1,609,138 alleles, total AF 4.35016e-06 (0.000435%), no homozygotes; highest subgroup AF 0.000165344 (0.01653%) in the Middle Eastern subgroup.
• gnomAD v2.1: 2/248,786 alleles, total AF 8.03904e-06 (0.000804%), no homozygotes; highest reported subgroup AF 1.76929e-05 (0.00177%) in the European non-Finnish subgroup.
• Generic population rule applied because no RAD51B-specific VCEP/CSPEC framework was retrieved: BA1 requires allele frequency >1%.

Sources

Reasoning

The observed population frequencies are below the generic BS1 threshold of >0.3%. The highest observed subgroup frequency is 0.000165344 (0.01653%) in gnomAD v4.1, and the gnomAD v4.1 grpmax FAF is 1.83e-06; gnomAD v2.1 also remains far below 0.3%.

Rule

Generic ACMG/AMP population threshold: BS1 is met only when allele frequency is >0.3%; no applicable RAD51B-specific specification was available.

Evidence considered

• gnomAD v4.1: total AF 4.35016e-06 (0.000435%), grpmax FAF 1.83e-06, and highest single subgroup AF 0.000165344 (0.01653%) in 1/6,048 Middle Eastern alleles.
• gnomAD v2.1: total AF 8.03904e-06 (0.000804%), grpmax FAF 2.94e-06, and highest reported subgroup AF 1.76929e-05 (0.00177%) in 2/113,040 European non-Finnish alleles.
• gnomAD-Canada v1.0 reports the variant as absent.
• Generic population rule applied because no RAD51B-specific VCEP/CSPEC framework was retrieved: BS1 requires allele frequency >0.3%.

Sources

Reasoning

BP6 is not met. The exact variant NM_133509.4:c.82C>G is reported as absent from ClinVar, with no exact-variant expert-panel Benign or Likely benign classification. No other source can trigger BP6 under the specified rule.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar exact-variant searching found no result for NM_133509.4:c.82C>G; therefore there is no exact-variant ClinVar expert-panel Benign/Likely benign assertion to support BP6.

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-level de novo evidence is available in the consolidated case-evidence bundle. The bundle contains no parental genotypes, parentage confirmation, trio testing, maternity/paternity information, or explicit de novo observation for NM_133509.4:c.82C>G (RAD51B; p.Gln28Glu). PS2 therefore cannot be applied.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with confirmed maternity and paternity for strong application; evidence is absent here.

Evidence considered

• The case summary identifies the variant as NM_133509.4:c.82C>G in RAD51B and reports no family or parental-testing data.
• The literature packet contains zero PMIDs and no publication-specific de novo evidence was available for review.

Still missing

• Documented proband genotype and phenotype
• Both parental genotypes for the variant
• Confirmed maternity and paternity or equivalent parentage evidence
• Testing methodology and coverage/quality for the proband and both parents

Reasoning

No ClinGen VCEP or gene-specific functional-assay framework is available for RAD51B in this case bundle (case_summary.cspec.found = false; vcep_materials.final_classification_framework.source = generic_acmg_fallback), so generic ACMG/AMP PS3 criteria were checked against the collected evidence. OncoKB was queried for variant-specific functional/oncogenic evidence but returned no variant-specific result (classification 'Unknown Oncogenic Effect', is_variant_specific=false, not_reviewed=true) -- only gene-level narrative that RAD51B is a homologous-recombination DNA repair protein altered by mutation in various cancers. No validated functional assay (e.g., HDR/homologous-recombination reporter assay, complementation assay, or other well-established RAD51B functional assay with documented normal/abnormal controls) addressing this specific variant (p.Gln28Glu) was identified in the prefetched sources, literature pass, or full-text map. No such assay data exists in the case bundle to evaluate for validation, concordance across replicates, or control performance.

Evidence considered

• OncoKB (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. RAD51B, a DNA repair protein involved in homologous recombination, is altered by mutation in various cancer types.' with is_variant_specific=false and not_reviewed=true, indicating no usable functional assay evidence for PS3.
• case_summary.cspec.found = false and vcep_materials.final_classification_framework.source = 'generic_acmg_fallback' confirm no RAD51B-specific VCEP functional-evidence specification governs this assessment; generic ACMG/AMP PS3 criteria were applied in evaluating available sources.

Still missing

• No variant-specific functional assay data (e.g., HR/HDR reporter assay, RAD51B complementation assay) identified for NM_133509.4:c.82C>G (p.Gln28Glu) in any source consulted (OncoKB, literature pass, full-text map).
• No ClinGen RAD51B/HR-gene VCEP functional-evidence specification available to define assay validation thresholds or PS3 strength calibration for this gene.
• OncoKB entry is gene-level only (RAD51B is a DNA repair/HR gene altered in cancer generally) and does not describe an assay result for this specific variant, so it cannot support PS3.

Reasoning

No case-control enrichment data, affected-case count, control count, statistical test, or independent affected-case series for NM_133509.4:c.82C>G (NP_598193.2:p.Gln28Glu) were available in the case-evidence bundle. PS4 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS4 requires a statistically significant excess of the variant in affected individuals compared with controls, or otherwise adequately documented disease-specific enrichment; no applicable RAD51B VCEP specification was retrieved.

Evidence considered

• The consolidated case-evidence bundle contains no case-control or variant-specific clinical series for this variant; its literature pass reports total_pmids=0.

Still missing

• Variant-specific affected-case and control counts are unavailable.
• No case-control effect estimate or statistical significance is available.
• No adequately documented independent affected-case series is available.

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 RAD51B VCEP or gene-specific framework is available. Under generic ACMG/AMP, PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual for a recessive disorder; the available case evidence contains no affected-proband observations, second-allele data, phase, or inheritance information.

Rule

Generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans with the variant under assessment in an affected individual; strength may be increased with multiple independent affected individuals or additional validated allelic evidence.

Evidence considered

• The case summary identifies RAD51B NM_133509.4:c.82C>G (NP_598193.2:p.(Gln28Glu)) and reports no ClinVar record or variant-specific literature evidence.
• The governing framework materials report that no CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP is therefore the applicable fallback.
• The consolidated evidence contains no family, pedigree, affected-proband, second-allele, phase, or inheritance observations relevant to PM3.

Still missing

• Affected-proband observations are not available.
• No pathogenic or likely pathogenic second variant is documented.
• Phase (trans versus cis) and inheritance mode are not documented.

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 unconfirmed de novo evidence is available in the consolidated case-evidence bundle. There is no report of the variant in an affected proband with an apparently negative family history, and no parental testing or parentage information is provided. PM6 therefore cannot be applied.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence without confirmation of maternity and paternity; evidence is absent here.

Evidence considered

• The case summary and evidence bundle provide no proband, family-history, or parental-testing record for this variant.
• The literature packet contains zero PMIDs and no publication-specific de novo evidence was available for review.

Still missing

• A documented de novo observation in an affected proband
• Parental genotypes or an explicit statement that parental testing was unavailable
• Phenotype and family-history documentation supporting the de novo interpretation

Reasoning

No segregation data are available in the consolidated case-evidence bundle. The record contains no pedigree, affected relatives, tested relatives, variant-carrier status, phenotype assessments, or number of informative meioses. PP1 cannot be applied or upgraded without documented cosegregation in an appropriate disease phenotype.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members, with strength determined by the number of informative meioses and study quality; evidence is absent here.

Evidence considered

• The consolidated case-evidence bundle contains no pedigree or family segregation observations for NM_133509.4:c.82C>G.
• No publication-specific segregation study was available; the literature packet reports zero PMIDs.

Still missing

• Pedigree with phenotype status for relatives
• Variant testing results for affected and unaffected relatives
• Number of informative meioses and segregation calculations
• Phenotype consistency and assessment of alternative explanations

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 case-evidence bundle does not provide a sufficiently specific phenotype, diagnostic criteria, or variant-specific genotype-phenotype correlation for the evaluated patient. PP4 cannot be assessed from the available evidence.

Rule

Generic ACMG/AMP PP4 may be considered only when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; the required phenotype documentation is absent.

Evidence considered

• The consolidated case-evidence bundle contains no patient phenotype description or phenotype-specific assessment for NM_133509.4:c.82C>G.

Still missing

• Detailed patient phenotype and diagnostic criteria are unavailable.
• The specificity of the phenotype for a RAD51B-associated disorder is not documented.
• No validated gene-disease or phenotype-specific framework was retrieved for RAD51B.

Reasoning

Population databases show no observed homozygotes, but the case bundle contains no clinical phenotype or study-level evidence demonstrating unaffected healthy adults carrying this variant, and no evidence of multiple healthy homozygotes. Absence of homozygotes alone is not evidence for BS2.

Rule

BS2 requires observation of the variant in healthy adults, typically including multiple homozygotes for a recessive condition or homozygotes for a dominant condition; allele-count data without phenotype ascertainment are insufficient.

Evidence considered

• gnomAD v4.1 reports 0 homozygotes overall and 0 homozygotes in the reported subgroups.
• gnomAD v2.1 reports 0 homozygotes overall and 0 homozygotes in the reported subgroups.
• The case bundle contains no variant-specific healthy-adult phenotype or homozygote observation study.

Still missing

• No curated healthy-adult carrier phenotype data were provided.
• No study documenting unaffected homozygous individuals was provided.
• The available gnomAD records report zero homozygotes but do not establish the BS2 clinical observation requirement.

Sources

Reasoning

As with PS3, no ClinGen VCEP or gene-specific functional-assay framework is available for RAD51B (generic_acmg_fallback), and no variant-specific functional assay data of any kind (normal-range/benign-concordant result) for NM_133509.4:c.82C>G was identified in OncoKB, the literature pass, or full-text sources. OncoKB returned only a gene-level, non-variant-specific summary with no assay classification. No functional study, published or otherwise, reporting a benign/wild-type-like functional readout for this specific variant was located.

Evidence considered

• OncoKB (oncokb) evidence_sentence confirms no variant-specific reviewed functional evidence exists (is_variant_specific=false, not_reviewed=true), so no benign-direction functional signal is available to support BS3.

Still missing

• No variant-specific functional assay data of any kind (benign or pathogenic direction) identified for this variant.
• No RAD51B VCEP functional-evidence specification available to define BS3 strength calibration or control benchmarks.

Reasoning

No non-segregation evidence is available in the consolidated case-evidence bundle. There are no tested unaffected relatives known to lack the variant, no pedigree, no phenotype definitions, and no informative meioses from which to assess BS4. BS4 therefore cannot be applied.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected family members, with appropriate consideration of phenotype, penetrance, age, and informative meioses; evidence is absent here.

Evidence considered

• The case summary and evidence bundle contain no unaffected-relative testing or non-segregation observations.
• No publication-specific non-segregation study was available; the literature packet reports zero PMIDs.

Still missing

• Tested unaffected relatives with reliable phenotype assessment
• Variant-negative results in informative relatives
• Pedigree structure and number of informative meioses
• Assessment of age-related penetrance and phenocopies

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 RAD51B VCEP or gene-specific framework is available. Under generic ACMG/AMP, BP2 requires the variant to be observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder; the available case evidence contains no second pathogenic variant, phase, affected-proband, or inheritance information.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder.

Evidence considered

• The case summary identifies RAD51B NM_133509.4:c.82C>G (NP_598193.2:p.(Gln28Glu)) and reports no ClinVar record or variant-specific literature evidence.
• The governing framework materials report that no CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP is therefore the applicable fallback.
• The consolidated evidence contains no family, pedigree, affected-proband, second-allele, phase, or inheritance observations relevant to BP2.

Still missing

• No pathogenic or likely pathogenic second variant is documented.
• Phase (trans versus cis) is not documented.
• Disease inheritance mode and affected-proband context are not documented.

Reasoning

No clinical case information establishes that the patient's phenotype is explained by an alternative pathogenic variant or molecular etiology while this variant is present. BP5 cannot be assessed.

Rule

Generic ACMG/AMP BP5 requires a pathogenic variant in an alternative gene that explains the phenotype; this criterion cannot be inferred from the absence of evidence for the evaluated variant.

Evidence considered

• The consolidated case-evidence bundle contains no documented alternate pathogenic variant, molecular diagnosis, or phenotype-level evidence for applying BP5.

Still missing

• The patient's complete variant findings are unavailable.
• No alternative pathogenic variant or definitive alternate molecular diagnosis is documented.
• No evidence links an alternative diagnosis to the patient's phenotype.