No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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 (Strong): truncating frameshift p.(Glu652ValfsTer69) escapes NMD but removes the second BRCT domain, a critical functional region.
Met (Moderate): essentially absent from population databases, with maximum subpopulation allele frequency 0.0001178 and no homozygotes.
No benign criterion marked as applied in the recorded assessment.
With no BARD1-specific gene framework available, generic ACMG/AMP 2015 rules were used: one strong (PVS1) plus one moderate (PM2) pathogenic criterion yields Likely Pathogenic.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 146 / 1,614,002 alleles. Recorded AF 9.04584e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 6.012e-05; MAF= 0.00601%, 17/282768 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116176; MAF= 0.01162%, 15/129114 alleles, homozygotes = 0); grpmax FAF= 8.103e-05.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
13 Pathogenic · 4 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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: 2 met · 2 not met · 14 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No PP3 or BP4 code is applied. The sole computational result is a neutral SpliceAI prediction, while the variant is a coding frameshift outside the scope of missense predictors.
No BARD1-specific ClinGen CSPEC/VCEP framework is available in the case bundle; generic ACMG/AMP criteria were therefore used.
Population data support PM2 at moderate strength under the generic ACMG/AMP framework, while the observed frequency is far below BA1 or BS1 thresholds and no qualifying BS2 observation is available.
No criteria match.
NM_000465.4 is the MANE Select/RefSeq Select BARD1 transcript. The 20-bp duplication is a frameshift in exon 10 that produces p.(Glu652ValfsTer69); the premature stop is in exon 11, the terminal exon, so the altered transcript is predicted to escape NMD. Although the predicted protein retains residues through 651, it replaces residues 652–720 with a frameshifted sequence and removes the C-terminal 57 residues. The exact variant has been reported to cause loss of BARD1's second BRCT domain. Functional complementation data show that BARD1 lacking the BRCT repeats (residues 602–777) fails to restore chromosomal stability and has substantially reduced homology-directed repair. With BARD1 loss of function established as a germline disease mechanism and no gene-specific PVS1 specification available, the generic ClinGen SVI PVS1 framework supports PVS1_Strong for this NMD-escaping truncation that disrupts a critical functional domain.
Generic ClinGen SVI PVS1 framework (PMC6185798): for an NMD-escaping truncating variant, use PVS1_Strong when the altered or deleted region is critical to protein function and loss of function is an established disease mechanism.
The variant is present only at an exceedingly low frequency in large population databases and is absent from gnomAD-Canada. gnomAD v4.1 reports AF 9.04584e-05 overall, maximum subpopulation AF 0.0001178, and zero homozygotes; gnomAD v2.1 reports AF 6.012e-05, maximum subpopulation AF 0.000116176, and zero homozygotes. This supports generic ACMG/AMP PM2 for a rare variant in a disease context where a pathogenic loss-of-function mechanism is established, without using another source's classification as evidence.
The variant does not meet the generic BA1 population-frequency threshold. Its maximum reported allele frequency is 0.0001178 in gnomAD v4.1 European (non-Finnish) individuals, with an overall frequency of 0.0000904584; these are far below a stand-alone benign threshold of 5%.
The observed population frequency is not higher than expected for BARD1-related cancer predisposition. The maximum observed AF is 0.0001178, and the overall gnomAD v4.1 AF is 0.0000904584. These frequencies are low and do not support a benign frequency observation under the generic BS1 criterion.
No proband-level de novo observation is documented in the case-evidence bundle. There is no confirmed maternity/paternity, parental genotype result, or explicit statement that the BARD1 variant arose de novo.
Generic ACMG/AMP PS2: confirmed de novo occurrence in a patient with the relevant phenotype and confirmed maternity and paternity; no qualifying case evidence is available.
No validated variant-specific functional assay was identified for NM_000465.4:c.1935_1954dup (p.(Glu652ValfsTer69)). The reviewed literature reports the variant as a truncating duplication and establishes that the BARD1 BRCT region is biologically important, but does not test this variant in a functional assay with appropriate controls. Therefore PS3 cannot be applied.
Generic ACMG/AMP functional-study rule: PS3 requires a well-established functional study showing a damaging effect for the variant; no qualifying variant-specific assay is available here.
No case-control enrichment statistic or adequately characterized case series versus controls was available for this exact variant. A reviewed source reports that the variant was identified during screening of non-BRCA1/2 breast or ovarian cancer families, but this observation alone does not establish statistically significant enrichment.
No applicable BARD1-specific VCEP framework was retrieved, so the generic ACMG/AMP framework was used. The case bundle documents this as a BARD1 germline cancer-predisposition variant, but provides no affected proband observations in a recessive disorder, no second pathogenic variant, and no validated phase information. The available literature identifies the exact variant in a familial breast/ovarian cancer screening context but does not establish a pathogenic variant in trans or a recessive inheritance pattern. PM3 therefore cannot be applied from the available evidence.
Generic ACMG/AMP PM3: pathogenic variants in trans with a pathogenic variant for a recessive disorder can support PM3; phase and the disease inheritance model must be established. No such evidence is available here.
No assumed de novo occurrence is reported for this variant. The available materials do not provide a patient-level observation, parental testing, or sufficient pedigree information to apply PM6.
Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with the relevant phenotype when maternity and paternity are not confirmed; no qualifying case evidence is available.
The available evidence does not document segregation of the exact variant through affected relatives across informative meioses. PMID:21344236 mentions a BARD1 protein-truncating mutation described as p.Glu652fs in a high-risk family, but explicitly does not name the queried c.1935_1954dup/p.(E652Vfs*69) variant and provides no usable individual-level segregation data for it.
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members in a gene known to cause the relevant disease; strength requires assessment of informative meioses and segregation data. No qualifying exact-variant segregation evidence is available.
The available evidence places the variant in breast or ovarian cancer family screening, but these cancer phenotypes are not sufficiently specific to BARD1-related predisposition to support PP4 under generic ACMG/AMP. No individual-level phenotype with a defined, highly specific BARD1 presentation was provided.
ClinVar contains exact-variant Pathogenic/Likely pathogenic laboratory submissions, but no expert-panel submission. Therefore PP5 cannot be applied.
No qualifying observation of the variant in healthy adults, unaffected individuals, or healthy homozygotes is documented. gnomAD contains heterozygous allele observations but does not establish individual health status for this variant, and no homozygotes are reported.
No validated variant-specific functional assay showing preserved normal function was identified. The available functional study concerns BARD1 BRCT-domain deletions rather than this variant and reports impaired activity, not a benign result for the specified allele. Therefore BS3 cannot be applied.
Generic ACMG/AMP functional-study rule: BS3 requires a well-established functional study showing no damaging effect for the variant; no qualifying variant-specific normal-function assay is available here.
No unaffected relatives tested for the exact variant, non-segregation observation, or phenotype-relevant family comparison is documented. Therefore BS4 cannot be assessed.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires appropriate affected relatives and a phenotype with sufficiently high penetrance. No qualifying family data are available.
No applicable BARD1-specific VCEP framework was retrieved, so the generic ACMG/AMP framework was used. The available case and literature materials do not report the queried variant in cis with a pathogenic variant or in trans with a pathogenic variant in a dominant disorder, and do not provide phase or co-occurrence data with a benign/neutral allele. Absence of a reported observation is insufficient to call BP2 not_met; the criterion remains not_assessed.
Generic ACMG/AMP BP2: observation of a variant in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder, may support benign evidence when the relevant inheritance model and phase are established. No qualifying observation is available here.
No evidence was provided that this variant was observed in an individual with an independent, established molecular diagnosis that fully explains the phenotype.
No exact-variant Benign or Likely benign ClinVar expert-panel assertion is present. Therefore BP6 cannot be applied.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000465.4:c.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000465.4:c.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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_missense
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.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). 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
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000465.4:c.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000465.4:c.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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_missense
NM_000465.4:c.1935_1954dup is a 20-bp coding frameshift, p.(Glu652ValfsTer69), not a missense SNV. SpliceAI shows no predicted splice alteration (maximum delta score 0.00), and no calibrated missense-predictor score is available or applicable. The neutral splice prediction does not constitute computational support for pathogenicity, and the frameshift consequence is assessed by loss-of-function criteria rather than PP3.
Generic ACMG/AMP PP3; not applicable to this frameshift because no calibrated computational evidence supports a deleterious splice effect and missense predictors are inapplicable.
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000465.4:c.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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_missense
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.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). 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
Although SpliceAI predicts no splice impact (maximum delta score 0.00), this does not predict no functional impact of the 20-bp coding frameshift p.(Glu652ValfsTer69). No calibrated benign missense-predictor evidence is applicable to this non-SNV. Therefore BP4 cannot be applied.
Generic ACMG/AMP BP4; not applicable because the available splice prediction addresses only splicing and no calibrated benign computational evidence is applicable to the frameshift consequence.
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.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). 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)139 / 1,179,966 | 0.00012 |
| African/African American3 / 75,038 | 4e-05 |
| Remaining individuals2 / 62,500 | 3.2e-05 |
| European (Finnish)2 / 64,010 | 3.1e-05 |
| European (non-Finnish)15 / 129,114 | 0.00012 |
| European (Finnish)2 / 25,102 | 8e-05 |
This variant is present in gnomAD v4.1 (AF= 9.04584e-05; MAF= 0.00905%, 146/1614002 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0001178; MAF= 0.01178%, 139/1179966 alleles, homozygotes = 0); grpmax FAF= 0.0001016.
This variant is present in gnomAD v2.1 (AF= 6.012e-05; MAF= 0.00601%, 17/282768 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116176; MAF= 0.01162%, 15/129114 alleles, homozygotes = 0); grpmax FAF= 8.103e-05.
Absent from gnomAD-Canada v1.0.
NM_000465.4:c.1935_1954dup is a 20-bp coding frameshift, p.(Glu652ValfsTer69), not a missense SNV. SpliceAI shows no predicted splice alteration (maximum delta score 0.00), and no calibrated missense-predictor score is available or applicable. The neutral splice prediction does not constitute computational support for pathogenicity, and the frameshift consequence is assessed by loss-of-function criteria rather than PP3.
Generic ACMG/AMP PP3; not applicable to this frameshift because no calibrated computational evidence supports a deleterious splice effect and missense predictors are inapplicable.
Although SpliceAI predicts no splice impact (maximum delta score 0.00), this does not predict no functional impact of the 20-bp coding frameshift p.(Glu652ValfsTer69). No calibrated benign missense-predictor evidence is applicable to this non-SNV. Therefore BP4 cannot be applied.
Generic ACMG/AMP BP4; not applicable because the available splice prediction addresses only splicing and no calibrated benign computational evidence is applicable to the frameshift consequence.
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.1935_1954dup in BARD1 is a frameshift variant predicted to produce NP_000456.2:p.(Glu652ValfsTer69). 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 = 0.00).
8 paper records listed. 2 cited in the classification.
These data indicate that both the ankyrin and BRCT motifs of BARD1 are necessary for suppression of both spontaneous and MMC-induced chromosomal instability.
Location Results, 'The Ankyrin and BRCT Motifs of BARD1 Are Necessary for Maintenance of Chromosomal Stability'; Table 1; Results, 'The RING, Ankyrin, and BRCT Motifs of BARD1 Are Each Necessary for Homology-directed Repair'
Context Functional complementation and DR-GFP/I-SceI homology-directed repair assays in Bard1-null mouse mammary carcinoma cell lines, including cells expressing full-length BARD1 or a BARD1 deletion lacking amino acids 602–777 containing the two BRCT repeats.
The screening of 196 non-BRCA1/2 breast or ovarian cancer families for BARD1 germline mutations identified eleven intron variants and fifteen exon variants, comprising nine missense mutations, four silent mutations, one in-frame deletion and one frame-shift duplication (c.1935_1954dup; p.E652Vfs*69) causing a premature stop and loss of the second BRCT domain of BARD1 (De Brakeleer et al., 2010).
Location Section 7.1.1.1, page 16
Context Screening of 196 non-BRCA1/2 breast or ovarian cancer families for germline BARD1 mutations; exon and intron variant identification.
Only two recent studies [12, 48] reported damaging mutations in BARD1 gene: a protein truncating mutation (p.Glu652fs) which was identified in a high-risk family and a heterozygous deletion of the whole BARD1 gene that was found in a breast cancer family.
Discussion, paragraph 2
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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= 9.04584e-05; MAF= 0.00905%, 146/1614002 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.0001178; MAF= 0.01178%, 139/1179966 alleles, homozygotes = 0); grpmax FAF= 0.0001016.
This variant is present in gnomAD v2.1 (AF= 6.012e-05; MAF= 0.00601%, 17/282768 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000116176; MAF= 0.01162%, 15/129114 alleles, homozygotes = 0); grpmax FAF= 8.103e-05.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Likely pathogenic (4 clinical laboratories). (ClinVarID = 127725)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.