No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.BARD1 encodes a protein that partners with BRCA1 to form a complex essential for repairing damaged DNA, particularly double-stranded breaks, and for maintaining genome stability through cell-cycle checkpoints and chromatin regulation. Germline mutations in BARD1 predispose to breast and ovarian cancer, among other cancers, and the gene is generally regarded as a tumor suppressor, although some evidence suggests it can also promote cancer in certain cellular contexts.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
No benign criterion marked as applied in the recorded assessment.
Variant of Uncertain Significance: no ACMG/AMP criterion was met, so no pathogenic or benign combination threshold was reached under the generic ACMG/AMP 2015 framework. Flagged for human review: criteria PM2, BA1, BS1, and BS2 remain unevaluated pending manual confirmation.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 7 / 1,614,006 alleles. Recorded AF 4.33703e-06. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.409. Refer to the recorded PP3/BP4 rationale for interpretation.
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 0 met · 7 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No ClinGen CSPEC or gene-specific VCEP framework exists for BARD1 (cspec found=false; vcep_materials.json domain_tables empty; generic ACMG fallback with precedence_rank 3), so generic ACMG/AMP 2015 (PMID 25741868) governs all five criteria in this group.
Residue-level criteria: p.(Glu429Lys) is not established as pathogenic anywhere in the case evidence (ClinVar VUS from 2 laboratories only), so PS1 is not met; no hotspot or curated critical-domain evidence places Glu429 in a PM1-relevant region, so PM1 is not met on available evidence; no alternate pathogenic missense at codon 429 was identified, but the same-residue search was incomplete (pm5_candidates mode 'unknown'), so PM5 is not assessed.
Gene-mechanism criteria (PP2, BP1) lack the required gene-level evidence: no missense-constraint metric or curated missense-vs-truncating variant spectrum for BARD1 is present, and the available LoF-mechanism context (pvs1_gene_context) is indirect; both are not assessed.
None of the fetched full-text papers in this case (PMID:17508274, PMID:31429903, PMID:34012068) mention BARD1 or this variant, so the literature contributes nothing to PS1/PM1/PM5/PP2/BP1.
This group contributes no positive or negative evidence to the final classification beyond the documented absence of same-residue/domain/mechanism support.
No BARD1 ClinGen/VCEP specification exists, so the generic ACMG/AMP 2015 (Richards et al., PMID 25741868) definitions of PS2, PM6, PP1, and BS4 were applied.
The case evidence contains no proband-parent trio, parental testing results, or pedigree segregation data, so no de novo (PS2/PM6) or segregation (PP1/BS4) determination is possible and all four criteria are recorded as not assessed.
ClinVar Variation ID 237817 reports the variant as Uncertain significance from two single-submitter clinical laboratories with no de novo, parental, or segregation assertions.
None of the full-text publications reviewed (PMID:17508274, PMID:31429903, PMID:34012068) mentions BARD1 or c.1285G>A, so no published de novo or segregation case for this variant exists in this evidence set.
Functional evidence group: no validated, well-established functional assay data for BARD1 p.(Glu429Lys) (c.1285G>A) are present in the evidence bundle; PS3 and BS3 are both not_assessed due to insufficient evidence.
This group contributes no pathogenic or benign functional evidence toward the final classification; a functional assay of p.Glu429Lys (per SVI calibration guidance, PMID:31112341) would be needed to change this.
Framework: generic ACMG/AMP 2015 (PMID 25741868). No ClinGen CSPEC/VCEP or local BARD1 gene-specific framework is available (cspec found=false; gene_vcep_dir null; framework_mode generic_acmg), so generic ACMG rules govern this group.
PS4 (case-control enrichment): not assessed - no case-control, cohort, or case-series data for BARD1 c.1285G>A exist in the bundle; ClinVar has only VUS submissions without counts, and all three full-text papers fetched for case observation do not mention BARD1 or the variant.
PP4 (phenotype specificity): not assessed - no proband-level phenotype/family-history data; aggregate ClinVar condition labels are insufficient, and breast/ovarian cancer susceptibility is not a highly specific single-etiology phenotype under generic ACMG rules.
PP5: not met - the only permitted trigger (exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification) is absent: variation 237817 has 0 expert-panel submissions and is VUS from 2 clinical laboratories.
BP5 (alternative molecular basis): not assessed - no case-level genotyping data permit testing for an alternative etiology in any carrier.
BP6: not met - the only permitted trigger (exact-variant ClinVar expert-panel Benign/Likely benign classification) is absent; all submissions are VUS.
Overall: no phenotype/prevalence evidence supports or opposes pathogenicity for this variant; the group contributes no met criteria. PP5/BP6 are determinatively not met because the ClinVar record contains no expert-panel assertion.
PM3 not_applicable: BARD1 germline cancer predisposition in this case is a heterozygous autosomal-dominant susceptibility context with no established biallelic/recessive disorder, and no pathogenic BARD1 allele is observed in trans with c.1285G>A in any source.
BP2 not_met: no observation of c.1285G>A in trans with a pathogenic variant (fully dominant disease) exists in ClinVar, gnomAD, or the reviewed literature; the benign-supporting criterion's required positive observation is absent.
Net effect on classification: the allelic group contributes no pathogenic (PM3) and no benign (BP2) evidence toward the final ACMG/AMP 2015 classification of NM_000465.4:c.1285G>A (p.Glu429Lys).
Framework: no ClinGen CSPEC/VCEP or gene-specific PP3/BP4 material exists for BARD1 in this case (cspec found=false, vcep_materials.json empty, gene_vcep_dir null); the generic ACMG/AMP 2015 fallback applies, whose in-silico calibration rule (generic_acmg_classification_rules.md) evaluates a missense variant with REVEL only and defines a gray zone [0.250, 0.750] in which neither PP3 nor BP4 is met.
REVEL score 0.409 for p.Glu429Lys falls squarely in the gray zone: it is not >0.750 (PP3 not met) and not <0.250 (BP4 not met). The same not-met verdict holds under the ClinGen SVI-calibrated REVEL cutoffs (PP3-supporting ~0.773; BP4-supporting <=0.016; Pejaver et al., PMID 36413997), so the call is threshold-robust.
BayesDel (0.092124) was excluded per the governing rule (no verified published threshold); SpliceAI max delta 0.01 was treated as context only for this exonic missense and was not used to support or refute PP3/BP4, avoiding double-counting the absence of predicted splice impact as protein-level evidence.
ClinVar laboratory commentary (e.g., Ambry's 'in silico prediction for this alteration is inconclusive') was not adopted as PP3/BP4 evidence, consistent with not inferring criteria from another source's classification or evidence statements.
All fetched full-text papers (PMID:17508274, PMID:31429903, PMID:34012068) were checked via paper_extracts.json; none mentions BARD1 or this variant, so no publication contributes PP3/BP4 evidence and none is cited for these criteria.
No criteria match.
Variant is BARD1 (NM_000465.4) c.1285G>A, NP_000456.2:p.(Glu429Lys). PS1 (generic ACMG/AMP 2015) requires that this same amino acid change has previously been established as pathogenic, typically via an alternate nucleotide change at the same codon. ClinVar variation 237817 classifies p.(Glu429Lys) as Uncertain significance from 2 clinical laboratories (Ambry Genetics SCV002689382; Labcorp/Invitae SCV000284906; review status 'criteria provided, single submitter'; 0 expert-panel submissions; 0 usable criterion-lead submissions). Neither submission asserts pathogenic/likely pathogenic, so the amino acid change is not established as pathogenic, and no alternate-nucleotide variant producing p.Glu429Lys with a P/LP assertion appears anywhere in the case evidence. PS1 is therefore not met.
PS1 (generic ACMG/AMP 2015, PMID 25741868): Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PM1 (generic ACMG/AMP 2015) requires the variant to lie in a mutational hot spot and/or a critical, well-established functional domain without benign variation. vcep_materials.json domain_tables is empty ({}) for BARD1, so no VCEP-approved critical-domain list was available and residue Glu429 could not be checked against an authoritative domain table. Available positional evidence is negative: the Cancer Hotspots query for BARD1 E429 returned no statistically significant hotspot ('This variant does not lie in a statistically significant hotspot'); COSMIC has no record of BARD1 c.1285G>A in somatic cancer; and OncoKB provides no variant-specific reviewed functional or domain-level evidence (Unknown Oncogenic Effect). No source in the case bundle positively places Glu429 within a critical functional domain of BARD1. On this evidence PM1 is not met, but the determination is limited because BARD1 domain architecture was not independently curated in this case.
PM1 (generic ACMG/AMP 2015): Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation.
BARD1 has no ClinGen CSPEC or gene-specific VCEP specification in this case (cspec found=false; framework_mode=generic_acmg), so the generic ACMG/AMP 2015 PP3/BP4 rule with this lab's generic operating calibration applies. Under that rule (generic_acmg_classification_rules.md), a missense variant is evaluated with REVEL only: REVEL >0.750 would support PP3, REVEL <0.250 would support BP4, and REVEL in [0.250, 0.750] is the defined gray zone in which neither criterion is met. NM_000465.4:c.1285G>A (BARD1, p.Glu429Lys) has REVEL 0.409, which lies inside the gray zone and therefore does not meet PP3; the same conclusion holds under the ClinGen SVI-calibrated REVEL PP3-supporting cutoff (>=0.773, Pejaver et al., PMID 36413997). The missense-path result is not cleared or modified by other predictors: SpliceAI max delta is 0.01 (no predicted splice impact, and the splice-predictor path is reserved for non-missense variants under the governing rule), and the BayesDel noAF score (0.092124) is excluded because no verified published threshold is available. No fetched literature mentions this variant, so no literature-based computational evidence exists. PP3 is therefore not met.
generic_acmg_fallback_pp3_bp4 (missense path): REVEL >0.750 -> PP3 supporting; REVEL 0.409 not >0.750 -> PP3 not met
Governing policy limits PP5 to an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger PP5. ClinVar variation 237817 has expert_panel_submissions = 0: both submissions are from clinical laboratories (Ambry Genetics; Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter' and classification Uncertain significance (2-star record, no expert panel). No exact-variant expert-panel P/LP classification exists, so PP5 is not met.
Governing policy: PP5 applies only to an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic (supporting strength); ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5.
BP2 (generic ACMG/AMP 2015, Richards et al., PMID 25741868) is met only when the variant is observed in trans with a pathogenic variant for a fully dominant disease/disorder. No such observation exists for NM_000465.4:c.1285G>A in any collected source: the two ClinVar submissions (Ambry SCV002689382; Labcorp/Invitae SCV000284906) are single-variant heterozygous germline VUS reports with no case-level phenotype detail, no second BARD1 variant, and no phase/co-occurrence data (usable_for_criterion_leads=0, validated_pmids=0); gnomAD population observations (7 het / 0 hom) carry no disease-context phase information; and the reviewed full-text papers do not mention BARD1 or this variant. Furthermore, BARD1-associated hereditary cancer predisposition is an incompletely penetrant heterozygous susceptibility model rather than a 'fully dominant' disorder in the classic BP2 sense. Because BP2 is a benign-supporting criterion requiring a positive trans-observation, the complete absence of that observation means the criterion is not met and contributes no benign evidence.
BP2 (generic ACMG/AMP 2015, Richards et al. PMID 25741868): 'Observed in trans with a pathogenic variant for a fully dominant disease/disorder' - required positive trans-observation is absent across all collected sources
Under the governing generic ACMG/AMP 2015 fallback (no CSPEC/VCEP exists for BARD1), BP4 for this missense variant requires REVEL <0.250 (supporting) per generic_acmg_classification_rules.md. The REVEL score for NM_000465.4:c.1285G>A (p.Glu429Lys) is 0.409, which is above the 0.250 BP4-supporting cutoff (and far above the ClinGen SVI-calibrated REVEL BP4-supporting cutoff of <=0.016, Pejaver et al., PMID 36413997), placing the variant in the framework-defined gray zone in which BP4 is not met. The absence of predicted splice impact (SpliceAI max delta 0.01) is a single splice-predictor line that, per the governing rule, does not clear the REVEL-assessed protein-level effect for a missense variant and would in any case not by itself constitute 'multiple lines of computational evidence suggesting no impact'; counting it as BP4 would double-count the same negative splice prediction. BayesDel (0.092124) is excluded for lack of a verified published threshold. No VCEP spreadsheet or literature pre-assigns or supports BP4 for this variant. BP4 is therefore not met.
generic_acmg_fallback_pp3_bp4 (missense path): REVEL <0.250 -> BP4 supporting; REVEL 0.409 not <0.250 -> BP4 not met
Governing policy limits BP6 to an exact-variant ClinVar expert-panel classification of Benign/Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6. ClinVar variation 237817 has expert_panel_submissions = 0 and both clinical-laboratory submissions are classified Uncertain significance - no Benign or Likely benign assertion of any kind exists, expert panel or otherwise. BP6 is not met.
Governing policy: BP6 applies only to an exact-variant ClinVar expert-panel classification of Benign/Likely benign (supporting strength); ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6.
No de novo occurrence of BARD1 c.1285G>A (p.Glu429Lys) with confirmed paternity and maternity has been reported in any available source; the ClinVar record (Variation ID 237817) contains two single-submitter VUS submissions with no parental testing or de novo assertions, and no proband-parent trio data exists in the case evidence, so PS2 cannot be assessed.
generic_acmg_2015 PS2: de novo occurrence (paternity and maternity confirmed)
PS3 (Richards et al. 2015, PMID:25741868) requires well-established functional studies demonstrating a deleterious effect of the variant, applied per SVI functional-evidence calibration (Brnich et al. 2019, PMID:31112341) only when the assay is validated against known variants with appropriate controls. BARD1 NM_000465.4:c.1285G>A (p.Glu429Lys) is an exon 4 missense variant for which no variant-specific functional assay data exist in this case: OncoKB's E429K entry reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence (not reviewed, no citations); neither ClinVar submission (Ambry SCV002689382, Labcorp SCV000284906, both VUS) cites any functional study; and the literature pass retrieved no functional-assay paper for BARD1, with full-text review of the three fetched papers confirming no mention of BARD1 or this variant. Evidence is therefore insufficient to determine a deleterious functional effect, so PS3 is not_assessed rather than met; absence of functional data is not evidence against PS3 and likewise cannot be repurposed as BS3. Adjudicated under the generic ACMG/AMP 2015 fallback because no BARD1 ClinGen CSPEC/VCEP specification exists.
generic_acmg_2015_PS3: well-established functional studies show a deleterious effect (Richards et al. 2015, PMID:25741868); requires validated assay evidence per SVI guidance (Brnich et al. 2019, PMID:31112341) - none available for this variant
No case-control or cohort enrichment evidence exists for BARD1 c.1285G>A (p.Glu429Lys) anywhere in the evidence bundle. ClinVar variation 237817 holds two 'criteria provided, single submitter' VUS submissions from clinical laboratories (Ambry Genetics; Labcorp/Invitae) with no affected/control counts, odds ratios, or enrichment analysis. The only full-text publications fetched for case-observation review (PMID:17508274 NSGC guideline, PMID:31429903 USPSTF statement, PMID:34012068 ACMG SF v3.0) do not mention BARD1 or this variant (variant_mentioned=false in paper_extracts). Generic ACMG/AMP 2015 PS4 cannot be applied; adjudication is not_assessed pending case-control or case-series data for this exact variant.
Generic ACMG/AMP 2015 PS4: prevalence of the variant in affected individuals is significantly increased relative to controls (strong evidence; typically OR >= 5 or equivalent statistically significant enrichment in a well-designed case-control study).
PM2 could not be assessed because its agent did not produce valid output.
PM5 (generic ACMG/AMP 2015) requires a different missense change at the same residue (BARD1 codon 429) that has been determined to be pathogenic. The pm5_candidates artifact for this case reports pm5_mode 'unknown' and eligible_for_classic_pm5_search=false, meaning the automatic same-residue comparator harvest was not performed; total_candidates_seen=0 and same_residue_candidates=0. ClinVar variation 237817 contains only this exact nucleotide change (p.Glu429Lys, VUS) and no alternate missense at codon 429. Because a systematic same-residue comparator search (ClinVar/LOVD/ENIGMA/literature) was not completed, the absence of candidates cannot be distinguished from an incomplete search, so evidence is insufficient to conclude PM5 is met or not met. PM5 is not assessed and must not be applied.
PM5 (generic ACMG/AMP 2015): Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
No assumed de novo occurrence (parental testing performed without confirmation of paternity and maternity) is documented for BARD1 c.1285G>A in ClinVar or in any reviewed publication, and no parental genotype data is present in the case evidence, so PM6 cannot be assessed.
generic_acmg_2015 PM6: assumed de novo, without confirmation of paternity and maternity
No co-segregation data in affected family members is available for BARD1 c.1285G>A: the case evidence contains no pedigree, no affected relatives tested for the variant, and no informative meioses, and none of the reviewed publications reports this variant, so PP1 cannot be assessed.
generic_acmg_2015 PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease
PP2 (generic ACMG/AMP 2015) requires (i) a low rate of benign missense variation in the gene and (ii) missense variants being a common mechanism of disease. No ClinGen CSPEC or gene-specific VCEP framework exists for BARD1 (cspec found=false; generic ACMG fallback in effect), and no local custom gene framework was supplied. The case bundle contains no gene-level missense-constraint metric (e.g., gnomAD missense Z-score or observed/expected ratio) and no curated distribution of pathogenic missense versus truncating variants for BARD1. The available pvs1_gene_context supports a loss-of-function/null germline mechanism for BARD1, which does not establish that missense is a common disease mechanism and is not itself a basis for applying PP2. Evidence is insufficient, so PP2 is not assessed.
PP2 (generic ACMG/AMP 2015): Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease.
Generic ACMG/AMP PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology. Only aggregate ClinVar condition labels ('Familial cancer of breast', 'Hereditary cancer-predisposing syndrome') are attached to variation 237817; the per-submission condition fields are empty and no proband-level phenotype or family-history detail is available. Hereditary breast/ovarian cancer susceptibility is not a highly specific single-etiology phenotype under the generic framework (no BARD1 VCEP rule exists to calibrate otherwise), and no case literature mentioning this variant is available to establish a distinctive phenotype. Evidence is insufficient; status not_assessed.
Generic ACMG/AMP 2015 PP4: phenotype or family history is highly specific for a disease with a single genetic etiology (supporting evidence for pathogenicity).
BA1 could not be assessed because its agent did not produce valid output.
BS1 could not be assessed because its agent did not produce valid output.
BS2 could not be assessed because its agent did not produce valid output.
BS3 (Richards et al. 2015, PMID:25741868) requires well-established functional studies demonstrating that the variant has no damaging effect on protein function or splicing, with the same assay-validation expectations as PS3 (SVI guidance, Brnich et al. 2019, PMID:31112341). No functional assay of BARD1 p.Glu429Lys exists anywhere in the collected evidence: OncoKB provides no variant-specific functional data, ClinVar submissions (both VUS) cite no functional studies, and no functional-assay literature was retrieved. The complete absence of functional data cannot be interpreted as evidence of a benign effect - absence of evidence is not BS3 - so BS3 is not_assessed rather than met. If validated assays later show wild-type-equivalent function for p.Glu429Lys, BS3 (supporting-to-strong per SVI calibration) could be reconsidered.
generic_acmg_2015_BS3: well-established functional studies show no damaging effect (Richards et al. 2015, PMID:25741868); requires validated assay evidence per SVI guidance (Brnich et al. 2019, PMID:31112341) - none available for this variant
No family-based non-segregation observations are available for BARD1 c.1285G>A (no affected family member tested without the variant, no pedigree data), so BS4 cannot be assessed; the rare gnomAD v4.1 carrier alleles are population-frequency observations addressed by BA1/BS1, not BS4 family-segregation evidence.
generic_acmg_2015 BS4: lack of segregation in affected family members
BP1 (generic ACMG/AMP 2015) requires that primarily truncating variants are known to cause disease in BARD1, such that a missense change is unlikely to be pathogenic. pvs1_gene_context.json supports a germline loss-of-function mechanism for BARD1 based on targeted literature (supporting sources include a case report describing a BARD1 frameshift, c.2229dup, co-occurring with a BMPR1A frameshift in a juvenile polyposis case, and a case series of patients with deleterious germline mutations including one BARD1 carrier). This context is indirect and does not establish, at the level required for BP1, that BARD1-associated disease is caused primarily by truncating variants with missense being non-pathogenic; the supporting sources largely concern LoF-eligible context rather than a curated benign-missense spectrum. Whether BARD1 qualifies as a 'primarily truncating' gene for BP1 is a gene-level expert judgment that cannot be resolved from this bundle. Evidence is insufficient, so BP1 is not assessed.
BP1 (generic ACMG/AMP 2015): Missense variant in a gene for which primarily truncating variants are known to cause disease.
Generic ACMG/AMP BP5 requires the variant to be found in a case where an alternative molecular basis of disease has been demonstrated. The evidence bundle contains no proband-level genotyping or phenotype data for any carrier of BARD1 c.1285G>A, and no case literature mentions this variant, so it cannot be determined whether any carrier has an alternative molecular explanation for their phenotype. Evidence insufficient; status not_assessed.
Generic ACMG/AMP 2015 BP5: variant found in a case with an alternative molecular basis for disease (supporting evidence for benignity).
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000465.4:c.1285G>A in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Glu429Lys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM3 as defined in the governing generic ACMG/AMP 2015 framework (Richards et al., PMID 25741868) applies only 'for recessive disorders, detected in trans with a pathogenic variant.' No ClinGen CSPEC/VCEP specification exists for BARD1 (cspec found=false, framework_mode=generic_acmg, precedence_rank 3), so the 2015 semantics govern. The disease context in this case is germline hereditary breast/ovarian cancer predisposition (ClinVar conditions 'Familial cancer of breast' and 'Hereditary cancer-predisposing syndrome'; germline loss-of-function disease literature summarized in pvs1_gene_context, e.g. heterozygous deleterious germline BARD1 carriers), a heterozygous autosomal-dominant susceptibility model; no biallelic/recessive BARD1 disorder is established in any collected source. PM3's structural precondition (a recessive disease model) therefore does not apply. Independently of the model question, no observation places c.1285G>A in trans with a pathogenic BARD1 allele: ClinVar VCV000237817 contains two heterozygous germline VUS submissions (Ambry SCV002689382; Labcorp/Invitae SCV000284906) with no second-variant or phase data (usable_for_criterion_leads=0, validated_pmids=0); gnomAD v4.1 shows 7 heterozygous alleles with 0 homozygotes; and none of the fetched full-text papers mention BARD1 or this variant.
PM3 (generic ACMG/AMP 2015, Richards et al. PMID 25741868): 'For recessive disorders, detected in trans with a pathogenic variant' - requires an established recessive disease model and an observed pathogenic allele in trans; structural precondition not met for this dominant-predisposition context
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000465.4:c.1285G>A in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Glu429Lys). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000465.4:c.1285G>A in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Glu429Lys). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000465.4:c.1285G>A in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Glu429Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in BARD1, mapped onto the exon structure of NM_000465.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)7 / 1,179,936 | 5.9e-06 |
This variant is present in gnomAD v4.1 (AF= 4.33703e-06; MAF= 0.00043%, 7/1614006 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93253e-06; MAF= 0.00059%, 7/1179936 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
BARD1 has no ClinGen CSPEC or gene-specific VCEP specification in this case (cspec found=false; framework_mode=generic_acmg), so the generic ACMG/AMP 2015 PP3/BP4 rule with this lab's generic operating calibration applies. Under that rule (generic_acmg_classification_rules.md), a missense variant is evaluated with REVEL only: REVEL >0.750 would support PP3, REVEL <0.250 would support BP4, and REVEL in [0.250, 0.750] is the defined gray zone in which neither criterion is met. NM_000465.4:c.1285G>A (BARD1, p.Glu429Lys) has REVEL 0.409, which lies inside the gray zone and therefore does not meet PP3; the same conclusion holds under the ClinGen SVI-calibrated REVEL PP3-supporting cutoff (>=0.773, Pejaver et al., PMID 36413997). The missense-path result is not cleared or modified by other predictors: SpliceAI max delta is 0.01 (no predicted splice impact, and the splice-predictor path is reserved for non-missense variants under the governing rule), and the BayesDel noAF score (0.092124) is excluded because no verified published threshold is available. No fetched literature mentions this variant, so no literature-based computational evidence exists. PP3 is therefore not met.
generic_acmg_fallback_pp3_bp4 (missense path): REVEL >0.750 -> PP3 supporting; REVEL 0.409 not >0.750 -> PP3 not met
Under the governing generic ACMG/AMP 2015 fallback (no CSPEC/VCEP exists for BARD1), BP4 for this missense variant requires REVEL <0.250 (supporting) per generic_acmg_classification_rules.md. The REVEL score for NM_000465.4:c.1285G>A (p.Glu429Lys) is 0.409, which is above the 0.250 BP4-supporting cutoff (and far above the ClinGen SVI-calibrated REVEL BP4-supporting cutoff of <=0.016, Pejaver et al., PMID 36413997), placing the variant in the framework-defined gray zone in which BP4 is not met. The absence of predicted splice impact (SpliceAI max delta 0.01) is a single splice-predictor line that, per the governing rule, does not clear the REVEL-assessed protein-level effect for a missense variant and would in any case not by itself constitute 'multiple lines of computational evidence suggesting no impact'; counting it as BP4 would double-count the same negative splice prediction. BayesDel (0.092124) is excluded for lack of a verified published threshold. No VCEP spreadsheet or literature pre-assigns or supports BP4 for this variant. BP4 is therefore not met.
generic_acmg_fallback_pp3_bp4 (missense path): REVEL <0.250 -> BP4 supporting; REVEL 0.409 not <0.250 -> BP4 not met
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000465.4:c.1285G>A in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Glu429Lys). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.409. BayesDel score = 0.092124.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 4.33703e-06; MAF= 0.00043%, 7/1614006 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.93253e-06; MAF= 0.00059%, 7/1179936 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 237817)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.409. BayesDel score = 0.092124.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.