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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations. 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 at very strong: the nonsense variant truncates BARD1 at p.Gln166 of 778 residues within an internal coding exon, supporting loss of function without a named downgrade.
Met at supporting strength: gnomAD v4.1 AF is 1.23947e-06 with zero homozygotes, below the PM2 threshold of <= 0.0001.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the generic ACMG/AMP 2015 fallback combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,613,598 alleles. Recorded AF 1.23947e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.98464e-06; MAF= 0.00040%, 1/250964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81135e-06; MAF= 0.00088%, 1/113490 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.067. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Pathogenic · 1 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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The variant is a nonsense change, p.(Gln166Ter), so both requested computational criteria are outside their governing generic scope; the available SpliceAI score is not used to override that scope.
Population evidence supports PM2 at supporting strength; BA1 and BS1 are not met because observed allele frequencies are orders of magnitude below their generic thresholds.
BS2 is not assessed because aggregate gnomAD allele counts do not document healthy adult status or the required full early-age penetrance condition.
No criteria match.
NM_000465.4:c.496C>T is a nonsense variant predicted to produce NP_000456.2:p.(Gln166Ter), truncating BARD1 at amino acid 166 of the 778-amino-acid reference protein. The supplied transcript model places c.496 within an internal coding exon rather than the terminal exon, so the premature stop is expected to be subject to nonsense-mediated decay and removes most of the protein sequence. BARD1 loss of function is supported as a germline disease mechanism in the supplied gene-level assessment. The transcript and consequence are directly established for the assessed BARD1 transcript, and no governing downgrade rule for NMD escape, a non-critical distal exon, or a repeat-region exception is evidenced. Therefore, the generic ACMG/AMP PVS1 definition is met at full strength: very strong.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Generic ACMG/AMP PM2 is met at supporting strength. The variant is rare in the default all-comers population sources: gnomAD v2.1 AF=3.98464e-06 (1/250,964 alleles; homozygotes=0) and gnomAD v4.1 AF=1.23947e-06 (2/1,613,598 alleles; homozygotes=0). Both are below the supplied PM2 supporting threshold of <= 0.0001. The gnomAD v2.1 non-cancer exome result is concordant at AF=4.22965e-06, and gnomAD v3.1 non-cancer is reported absent.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The governing ACMG/AMP PS4 rule requires the variant prevalence in affected individuals to be significantly increased compared with controls; the supplied case-control evidence is for aggregated BARD1 pathogenic/likely pathogenic alterations, not this exact variant, and reports a standardized risk ratio of 1.28 with 95% CI 0.55–2.51. The exact operator in the governing rule is >5.0: 1.28 > 5.0? no. The confidence interval includes 1.0, so the PS4 note is not satisfied. The exact variant NM_000465.4:c.496C>T (p.Gln166Ter) was not reported in the study.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The generic PP5 rule is restricted to an exact-variant ClinVar expert-panel classification supporting pathogenicity. The exact ClinVar record for NM_000465.4:c.496C>T (p.Gln166Ter) has no expert-panel submissions; its Pathogenic assertions are single-submitter laboratory classifications. Therefore PP5 is not met.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6.
Generic ACMG/AMP BA1 is not met. The variant's maximum reported allele frequency is 4.22965e-06 in gnomAD v2.1 non-cancer exomes, while the default all-comers gnomAD totals are 3.98464e-06 in v2.1 and 1.23947e-06 in v4.1; all are far below the generic stand-alone threshold of >= 0.05. No homozygotes were observed. Because no VCEP governs BARD1, the all-comers totals are the default source, with the non-cancer exome result providing concordant population evidence.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
Generic ACMG/AMP BS1 is not met. The default all-comers gnomAD v2.1 and v4.1 allele frequencies are 3.98464e-06 and 1.23947e-06, respectively, and the maximum observed subgroup frequencies are 8.81135e-06 and 1.69506e-06; each is below the supplied generic BS1 threshold of >= 0.01. The non-cancer v2.1 exome frequency is also only 4.22965e-06.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The generic BP6 rule is restricted to an exact-variant ClinVar expert-panel classification supporting benignity. The exact ClinVar record for NM_000465.4:c.496C>T (p.Gln166Ter) has no expert-panel submissions and reports Pathogenic, not Benign/Likely benign, laboratory classifications. Therefore BP6 is not met.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6.
The available case evidence does not document that NM_000465.4:c.496C>T arose de novo in the proband, does not provide testing of both biological parents, and does not establish absence of a relevant family history. The reviewed variant-focused literature does not report this exact variant or parental testing. Therefore, the requirements for PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The variant is NM_000465.4:c.496C>T (p.Gln166Ter), but the reviewed literature provides no variant-specific in vitro or in vivo functional assay for this change. PMID:20077502 examined another BARD1 truncating variant with leukocyte RNA analysis, and PMID:21344236 described other BARD1 variants and general loss-of-function biology; neither tested c.496C>T. OncoKB's likely loss-of-function label and ClinVar pathogenic submissions are interpretations, not validated functional-study results. Therefore, the evidence does not establish PS3 at any strength under the generic ACMG/AMP definition.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
The available case evidence does not document an assumed de novo occurrence of NM_000465.4:c.496C>T in the proband, negative parental testing, or a family history consistent with de novo inheritance. The reviewed literature does not report this exact variant. Therefore, PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No affected relatives carrying NM_000465.4:c.496C>T, unaffected relatives lacking it, or meioses supporting cosegregation are documented in the available case evidence. The reviewed BARD1 family studies concern different variants and cannot establish segregation for this variant. Therefore, PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The governing PP4 rule requires a patient's phenotype or family history that is highly specific for a disease with a single genetic etiology. The supplied evidence does not provide a patient phenotype or family-history description for this case that permits that specificity assessment.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available population data. gnomAD contains one heterozygous allele in v2.1 and two heterozygous alleles in v4.1, with no homozygotes, but these aggregate records do not document that a carrier was a healthy adult, establish the relevant phenotype, or demonstrate full penetrance expected at an early age. The available evidence therefore does not satisfy the specific healthy-adult observation requirement for BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No reviewed study tested NM_000465.4:c.496C>T (p.Gln166Ter) in a validated assay demonstrating preserved protein function or normal splicing. PMID:20077502 reported RNA findings for a different BARD1 truncating variant, while PMID:21344236 reported other variants and did not provide functional data for this variant. The available evidence therefore cannot support BS3 or its benign direction at any strength.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The available case evidence does not identify affected family members who were tested and found not to carry NM_000465.4:c.496C>T. No variant-specific non-segregation, pedigree, or phenotype data are documented, so lack of segregation cannot be established.
Lack of segregation in affected members of a family.
The available evidence does not report whether NM_000465.4:c.496C>T is in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant. No parent, offspring, tumor, or other phase-testing result is provided, so BP2 cannot be assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied case evidence does not identify an alternate molecular diagnosis in the case, so BP5 cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers PS1 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers PM1 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PM3 is limited to recessive disorders. The available case evidence identifies BARD1-related cancer predisposition but does not establish a recessive disorder context, so this criterion is not applicable; no trans observation can be used for PM3.
For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers PM4 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers PM5 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers PP2 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_000465.4:c.496C>T is a nonsense variant, p.(Gln166Ter), and the governing generic scope excludes nonsense and other truncating or protein-length-changing variants; therefore neither REVEL nor SpliceAI is evaluated for PP3.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers BP1 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers BP3 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_000465.4:c.496C>T is a nonsense variant, p.(Gln166Ter), and the governing generic scope excludes nonsense and other truncating or protein-length-changing variants; therefore the available SpliceAI score is not evaluated for BP4.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers BP7 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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)2 / 1,179,896 | 1.7e-06 |
| European (non-Finnish)1 / 113,490 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 1.23947e-06; MAF= 0.00012%, 2/1613598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69506e-06; MAF= 0.00017%, 2/1179896 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.98464e-06; MAF= 0.00040%, 1/250964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81135e-06; MAF= 0.00088%, 1/113490 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
PP3 is not applicable because NM_000465.4:c.496C>T is a nonsense variant, p.(Gln166Ter), and the governing generic scope excludes nonsense and other truncating or protein-length-changing variants; therefore neither REVEL nor SpliceAI is evaluated for PP3.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
BP4 is not applicable because NM_000465.4:c.496C>T is a nonsense variant, p.(Gln166Ter), and the governing generic scope excludes nonsense and other truncating or protein-length-changing variants; therefore the available SpliceAI score is not evaluated for BP4.
PP3/BP4 apply only to a missense variant, or to a splice-region/intronic variant via the SpliceAI path - never to a frameshift, nonsense, or other truncating/protein-length-changing variant.
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.496C>T in BARD1 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000456.2:p.(Gln166Ter). 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. No VCEP criteria specification covers BP7 for BARD1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.60222.
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.
Similar to BRCA1 mutations, BARD1 mutations have been identified in individuals with sporadic and hereditary tumours8,9.
Domain organization of BRCA1, paragraph discussing BARD1
Absence of BARD1 is deleterious to a cell; homozygous Bard1-null mice show early embryonic lethality, and cells from these mice possess genomic instability.
Introduction; Results, Table 1 and paragraph describing c.1690C>T; Discussion
Furthermore, associations with OC were not observed for BARD1, CHEK2, MRE11A, and RAD50.
Results, paragraph 2; Table 2; Discussion, paragraph 4
Finally, we report for the first time a protein truncating mutation in BARD1 (p.Glu652fs) causing the removal of an important functional domain: the second BRCT domain. Nonsense mediated decay was not observed in leucocytes from mutation carriers, suggesting that truncated BARD1 protein might accumulate in breast epithelial cells from these persons.
Discussion, final paragraph concerning p.Glu652fs; Results, paragraph beginning “Finally, we observed for the first time a protein truncating mutation in BARD1.”
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= 1.23947e-06; MAF= 0.00012%, 2/1613598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69506e-06; MAF= 0.00017%, 2/1179896 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 3.98464e-06; MAF= 0.00040%, 1/250964 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81135e-06; MAF= 0.00088%, 1/113490 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 185846)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.60222.
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.