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.
Met, supporting: gnomAD v4.1 AF 5.11611e-05 is below the PM2 threshold of <=0.0001, although gnomAD-Canada reports 0.0002716505.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) was the only applied criterion, which does not meet a generic ACMG/AMP benign or pathogenic combination threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 79 / 1,544,142 alleles. Recorded AF 5.11611e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.86024e-05; MAF= 0.00386%, 7/181336 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19166e-05; MAF= 0.00919%, 7/76156 alleles, homozygotes = 0); grpmax FAF= 4.241e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
Recorded SpliceAI maximum delta score: 0.002. Refer to the recorded PP3/BP4 rationale for interpretation.
5 Uncertain significance · 4 Likely benign · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All five requested codon-, residue-, domain-, and missense-mechanism criteria are not applicable because NM_000465.4:c.-4G>A is a 5' untranslated-region variant with protein consequence NP_000456.2:p.?.
No BARD1-specific VCEP framework was retrieved; generic ACMG/AMP criteria definitions were used where applicable.
PS4, PP4, and BP5 remain not assessed because the case lacks the required clinical or case-level evidence.
PP5 and BP6 are not met because ClinVar variation 184470 has no exact-variant expert-panel classification.
No applicable BARD1-specific VCEP or gene-specific framework was available; generic ACMG/AMP rules were therefore used.
The variant is rare in the default all-comers gnomAD v2.1 and v4.1 datasets, with zero observed homozygotes; it is far below BA1 and BS1 thresholds.
PM2 is assigned at supporting strength from the default gnomAD datasets, but the higher gnomAD-Canada frequency makes cohort applicability a human-review issue.
No criteria match.
PM2 is met at supporting strength using the default all-comers gnomAD datasets. The variant has AF 3.86024e-05 in gnomAD v2.1 (7/181336 alleles) and AF 5.11611e-05 in gnomAD v4.1 (79/1544142 alleles), both below the supplied PM2 supporting threshold of <=0.0001; the highest reported gnomAD v4.1 ancestry AF is 6.53212e-05. gnomAD-Canada reports a higher AF of 0.0002716505, so the result warrants human review for cohort applicability and threshold handling, but no governing VCEP specification requires that cohort to replace the default gnomAD sources.
Generic PM2 supporting: allele frequency <=0.0001 in an appropriate population dataset; default all-comers gnomAD v2.1 and v4.1 qualify, subject to review of the higher gnomAD-Canada cohort frequency.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 184470 is an exact transcript match, but the record reports zero expert-panel submissions and only ordinary laboratory submissions with conflicting Uncertain significance, Likely benign, and Benign classifications. Consequently, the required expert-panel pathogenic or likely pathogenic assertion is absent and PP5 is not met.
Apply PP5 only when the exact variant has a ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
BA1 is not met. The variant frequency is 3.86024e-05 (7/181336 alleles) in gnomAD v2.1 and 5.11611e-05 (79/1544142 alleles) in gnomAD v4.1, with the highest reported gnomAD v4.1 ancestry frequency 6.53212e-05 in the European non-Finnish population. All are far below the generic ACMG stand-alone benign threshold of >=0.05 from Richards et al. 2015 (PMID:25741868).
Generic ACMG/AMP BA1: allele frequency >=0.05; no applicable BARD1-specific VCEP specification was available.
BS1 is not met. The variant frequency is 3.86024e-05 in gnomAD v2.1 and 5.11611e-05 in gnomAD v4.1; the highest reported gnomAD v4.1 ancestry frequency is 6.53212e-05, all below the generic BS1 threshold of >=0.01. gnomAD-Canada reports a higher AF of 0.0002716505, but this also remains below 0.01 and does not meet BS1.
Generic ACMG/AMP BS1: allele frequency >=0.01; no applicable BARD1-specific VCEP specification was available.
BS2 is not met. gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada each report zero homozygotes for the variant. The available evidence documents heterozygous population observations but does not establish the variant in healthy adults as homozygous or otherwise provide the healthy-individual genotype evidence required for BS2.
Generic ACMG/AMP BS2 requires occurrence in healthy adults in a genotype relevant to the disease mechanism, such as homozygous occurrence for a dominant disorder; this case has no qualifying observation.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 184470 is an exact transcript match, but the record reports zero expert-panel submissions and the Benign/Likely benign assertions are from ordinary laboratory submissions. Therefore, no qualifying expert-panel benign or likely benign assertion exists and BP6 is not met.
Apply BP6 only when the exact variant has a ClinVar expert-panel classification of Benign or Likely benign; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
PS2 cannot be assessed because no documented de novo occurrence is provided for BARD1 NM_000465.4:c.-4G>A. The available materials do not identify a proband with this variant plus confirmed absence in both biological parents, nor do they provide parental testing results, maternity/paternity confirmation, or validated phenotype-consistent de novo observations.
Generic ACMG/AMP PS2: confirmed de novo occurrence in an affected individual with confirmed maternity and paternity; strength depends on the quality and number of de novo observations, and no gene-specific framework was available.
No validated functional assay evidence was identified for NM_000465.4:c.-4G>A in the reviewed case materials. The variant is a 5' UTR substitution with predicted protein consequence p.(=), and the available SpliceAI result (maximum delta 0.002) is computational rather than experimental; therefore PS3 cannot be assigned at any strength.
No applicable BARD1 VCEP framework was retrieved, so generic ACMG/AMP guidance applies. PS4 requires case-control enrichment or multiple affected individuals with the disease; the available record contains no case-control counts, odds ratio, affected-carrier count, or variant-specific affected-case series for NM_000465.4:c.-4G>A. The ClinVar record contains conflicting ordinary laboratory submissions and is not case-control evidence. Therefore PS4 cannot be assessed from the available evidence.
Generic ACMG/AMP PS4: disease-causing variants are observed at significantly increased frequency in affected individuals compared with controls, or in multiple affected individuals with the same disease; no applicable BARD1-specific rule was retrieved.
No affected-proband observation, biallelic genotype, pathogenic or likely pathogenic variant in trans, homozygous state, or phase-confirmed allelic evidence is documented for BARD1 NM_000465.4:c.-4G>A. The available case evidence contains population, ClinVar, and prediction records but no family-level or individual-level phasing data; therefore PM3 cannot be assessed rather than treated as absent.
Generic ACMG/AMP PM3: pathogenic or likely pathogenic variant observed in trans with the variant under assessment in an affected individual, with strength determined by the applicable validated framework; no gene-specific framework was available.
PM6 cannot be assessed because no assumed de novo occurrence is documented for BARD1 NM_000465.4:c.-4G>A. There is no reported affected proband with an apparently de novo variant lacking confirmed parental testing, and no supporting family, phenotype, or meiosis information is available.
Generic ACMG/AMP PM6: assumed de novo occurrence in an affected individual when parental testing is unavailable or incomplete; strength depends on the supporting clinical and family evidence, and no gene-specific framework was available.
PP1 cannot be assessed because no affected relatives carrying BARD1 NM_000465.4:c.-4G>A are documented. The materials provide no informative meioses, phase-resolved familial genotypes, phenotype-segregation data, or count of affected and unaffected tested relatives from which supporting, moderate, or strong segregation evidence could be assigned.
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; strength is determined by the number and informativeness of meioses and the applicable validated calibration, and no gene-specific framework was available.
No applicable BARD1 VCEP framework was retrieved, so generic ACMG/AMP guidance applies. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single-gene etiology. The available evidence does not provide a phenotype, clinical presentation, family history, or variant-specific phenotype correlation for this case. General BARD1 cancer-management literature does not establish a phenotype for this individual.
Generic ACMG/AMP PP4: patient's phenotype or family history is highly specific for a disease with a single-gene etiology; no applicable BARD1-specific rule was retrieved.
No validated functional assay demonstrating a normal or benign effect of NM_000465.4:c.-4G>A was identified. The low SpliceAI maximum delta of 0.002 is an in-silico prediction and cannot establish normal functional performance; therefore BS3 cannot be assigned at any strength.
BS4 cannot be assessed because no informative unaffected relatives have been tested for BARD1 NM_000465.4:c.-4G>A. The materials do not provide a pedigree, ages and phenotypes of relatives, genotype results in unaffected individuals, or sufficient penetrance and ascertainment information to distinguish non-segregation from age-dependent or incomplete expression.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires informative family testing and consideration of age-dependent or incomplete penetrance, and no gene-specific framework was available.
No individual-level observation is documented in which BARD1 NM_000465.4:c.-4G>A co-occurs with a known pathogenic or likely pathogenic variant in trans, or with another variant in cis where BP2 would be applicable. ClinVar and the available literature materials provide no qualifying co-occurrence or phase evidence; therefore BP2 cannot be assessed rather than treated as absent.
Generic ACMG/AMP BP2: observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant for a recessive disorder, subject to disease mechanism and validated framework; no gene-specific framework was available.
No applicable BARD1 VCEP framework was retrieved, so generic ACMG/AMP guidance applies. BP5 requires the variant to be found in a case with an alternate molecular basis for the disease. The available materials provide no affected-case report linking this exact variant to a disease presentation together with an established alternate molecular diagnosis. The conflicting ordinary ClinVar classifications and population observations do not constitute BP5 evidence.
Generic ACMG/AMP BP5: variant found in a case with an alternate molecular basis for disease; no applicable BARD1-specific rule was retrieved.
No applicable VCEP or gene-specific framework was available, so the generic ClinGen SVI PVS1 framework applies. NM_000465.4:c.-4G>A is a 5′-UTR SNV with consequence classified as unknown, no protein consequence (NP_000456.2:p.?), no exon assignment, and no nonsense, frameshift, or canonical ±1,2 splice-site effect. It therefore does not enter a PVS1 loss-of-function null-variant category; NMD, exon-importance, and protein-length-change downgrades are not applicable.
Generic ClinGen SVI PVS1 framework (PMC6185798): PVS1 applies to qualifying loss-of-function null variants; a 5′-UTR SNV with p.? is outside the default nonsense, frameshift, and canonical splice-site categories.
PS1 is not applicable because NM_000465.4:c.-4G>A is a 5' untranslated-region substitution with protein consequence NP_000456.2:p.?; it does not encode an amino-acid change for comparison with an established same-amino-acid pathogenic variant.
PM1 is not applicable because the variant is a 5' untranslated-region substitution with protein consequence NP_000456.2:p.?; no missense residue can be assessed against a critical functional domain or hotspot.
PM4 concerns an in-frame protein length change caused by an insertion or deletion, or another established protein-length alteration. NM_000465.4:c.-4G>A is a 5′-UTR SNV with NP_000456.2:p.? and no documented amino-acid sequence or protein-length change, so PM4 is not applicable.
Generic ACMG/AMP PM4: an established protein-length change, such as an in-frame indel, is required; this 5′-UTR SNV has no protein-length consequence.
PM5 is not applicable because NM_000465.4:c.-4G>A does not produce a defined amino-acid substitution; therefore, alternate pathogenic substitutions at the same codon or residue cannot be compared.
PP2 is not applicable because this is not a missense variant; the 5' untranslated-region substitution has no amino-acid consequence on which to assess the gene's missense mechanism.
PP3 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant in exon 1 with predicted protein consequence p.(=), not a missense, intronic, or splice-region variant. The scope rule excludes this variant before evaluating SpliceAI, REVEL, or any other computational predictor.
BP1 is not applicable because it is restricted to missense variants in genes for which pathogenic disease is primarily caused by truncating variants; NM_000465.4:c.-4G>A is a 5' untranslated-region substitution, not a missense variant.
BP3 applies to an in-frame insertion or deletion in a repetitive region without a known function. NM_000465.4:c.-4G>A is a 5′-UTR SNV, not an in-frame insertion or deletion, and the case evidence documents no repeat-region protein alteration; therefore BP3 is not applicable.
Generic ACMG/AMP BP3: an in-frame insertion or deletion in a repetitive region with no known function is required; this noncoding SNV does not meet that scope.
BP4 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant in exon 1 with predicted protein consequence p.(=), not a missense, intronic, or splice-region variant. The scope rule excludes this variant before evaluating SpliceAI, REVEL, or any other computational predictor.
BP7 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant, not a synonymous coding variant. Although the normalized protein consequence is p.(=), the variant lies upstream of the coding sequence and therefore does not meet BP7's synonymous-variant scope.
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)75 / 1,148,172 | 6.5e-05 |
| Remaining individuals2 / 60,000 | 3.3e-05 |
| Admixed American1 / 52,478 | 1.9e-05 |
| African/African American1 / 73,214 | 1.4e-05 |
| European (non-Finnish)7 / 76,156 | 9.2e-05 |
This variant is present in gnomAD v4.1 (AF= 5.11611e-05; MAF= 0.00512%, 79/1544142 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.53212e-05; MAF= 0.00653%, 75/1148172 alleles, homozygotes = 0); grpmax FAF= 5.336e-05.
This variant is present in gnomAD v2.1 (AF= 3.86024e-05; MAF= 0.00386%, 7/181336 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19166e-05; MAF= 0.00919%, 7/76156 alleles, homozygotes = 0); grpmax FAF= 4.241e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
PP3 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant in exon 1 with predicted protein consequence p.(=), not a missense, intronic, or splice-region variant. The scope rule excludes this variant before evaluating SpliceAI, REVEL, or any other computational predictor.
BP4 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant in exon 1 with predicted protein consequence p.(=), not a missense, intronic, or splice-region variant. The scope rule excludes this variant before evaluating SpliceAI, REVEL, or any other computational predictor.
BP7 is not applicable because NM_000465.4:c.-4G>A is a 5-prime UTR variant, not a synonymous coding variant. Although the normalized protein consequence is p.(=), the variant lies upstream of the coding sequence and therefore does not meet BP7's synonymous-variant scope.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 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.
In general, the Panel favored consideration of risk-reducing mastectomy for women harboring highly penetrant genes (e.g. BRCA1, BRCA2, TP53, and PALB2), and surveillance with mammography and magnetic resonance imaging (MRI), for women with intermediate penetrance genes (e.g. BARD1, CHEK2, CDH1, STK11).
Genetic testing and management of hereditary breast cancers and syndromes, paragraph 2
The guidelines are intended to provide background information about the process of genetic counseling and risk assessment for hereditary cancer rather than to provide information about specific hereditary cancer syndromes.
Purpose, p. 84
While being developed for reclassification of BRCA1 and BRCA2 variants, the history weighting algorithm is expected to be applicable to other cancer- and non-cancer-related genes.
Abstract
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
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= 5.11611e-05; MAF= 0.00512%, 79/1544142 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.53212e-05; MAF= 0.00653%, 75/1148172 alleles, homozygotes = 0); grpmax FAF= 5.336e-05.
This variant is present in gnomAD v2.1 (AF= 3.86024e-05; MAF= 0.00386%, 7/181336 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.19166e-05; MAF= 0.00919%, 7/76156 alleles, homozygotes = 0); grpmax FAF= 4.241e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.00027165054873410846, 5/18406 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 184470)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant has not previously been reported in somatic cancers (COSMIC).