The BARD1 NM_000465.4:c.842C>T (NP_000456.2:p.(Pro281Leu)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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 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 supporting strength: gnomAD v4.1 all-comers AF=3.35149e-05, below the PM2 threshold of <= 0.0001.
Met at supporting strength: missense REVEL 0.066 meets the generic BP4 threshold of <=0.29.
VUS: PM2 supporting and BP4 supporting are applied, but together they satisfy neither a pathogenic nor a benign ACMG/AMP combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 54 / 1,611,222 alleles. Recorded AF 3.35149e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 5.36538e-05; MAF= 0.00537%, 15/279570 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000607386; MAF= 0.06074%, 15/24696 alleles, homozygotes = 0); grpmax FAF= 0.00029888.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.066. Refer to the recorded PP3/BP4 rationale for interpretation.
8 Likely benign · 6 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.
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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The queried variant is BARD1 p.Pro281Leu. PS1 is not met because the only same-amino-acid paper comparator was classified as a VUS rather than pathogenic.
PM1, PM5, PP2, and BP1 remain not assessed because the supplied evidence lacks the criterion-specific domain, pathogenic same-residue, gene-level missense, or variant-spectrum evidence required by the generic definitions.
No VCEP covers BARD1 in this case; generic ACMG/AMP 2015 definitions govern.
The exact queried variant is NM_000465.4:c.842C>T (p.Pro281Leu); a literature report using c.421C>T with the same protein change was not treated as the same exact variant.
ClinVar expert-panel status was applied strictly: zero expert-panel submissions means ordinary laboratory classifications cannot trigger PP5 or BP6.
For this missense variant, the generic rules require the REVEL path and prohibit substituting the SpliceAI result; REVEL 0.066 supports BP4 at supporting strength and does not meet PP3.
No criteria match.
PM2 is met at supporting strength. Under the generic default, the allele frequency is at or below 0.0001 in the relevant population datasets: gnomAD v4.1 all-comers AF=3.35149e-05 (54/1611222) and gnomAD v2.1 all-comers AF=5.36538e-05 (15/279570), with zero homozygotes in both. The gnomAD v2.1 non-cancer exome subset also has AF=3.85195e-05 (9/233648), supporting the same conclusion.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; the SpliceAI score is not used for missense BP4. REVEL is 0.066, which is at or below the supplied generic BP4 supporting threshold of <=0.29, supporting BP4 at supporting strength. The BayesDel score is not used because no generic ACMG-strength calibration is established for BayesDel.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The queried variant is BARD1 NP_000456.2:p.(Pro281Leu). PMID:32959997 reports a BARD1 p.(Pro281Leu) entry, but the coding change is c.421C>T rather than the queried c.842C>T and the paper classifies it as a variant of unknown significance, not a previously established pathogenic variant. Therefore the required pathogenic same-amino-acid comparator for PS1 is absent.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; splice prediction is not used for missense PP3/BP4. REVEL is 0.066, below the supplied generic PP3 supporting threshold of >=0.644, and therefore does not support PP3 at any strength. BayesDel is not usable because no generic ACMG-strength calibration is established for it.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent
ClinVar contains no exact-variant expert-panel classification for NM_000465.4:c.842C>T: the audit reports zero expert-panel submissions and only ordinary laboratory submissions, with Likely benign and Uncertain significance classifications. Because generic PP5 requires a reputable pathogenic report and the supplied ClinVar evidence is not an expert-panel pathogenic assertion, PP5 is not met.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The highest observed allele frequency is 0.000695578 in the African/African American population in gnomAD v4.1, with an all-comers allele frequency of 3.35149e-05 (54/1611222); both are far below the generic stand-alone threshold of >= 0.05. gnomAD v2.1 likewise shows an all-comers allele frequency of 5.36538e-05 (15/279570).
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met under the generic default. The highest observed allele frequency is 0.000695578 in African/African American individuals in gnomAD v4.1, and the all-comers frequency is 3.35149e-05; these are below the generic 0.01 default. The ancestry-specific elevation is therefore not sufficient by itself to establish an allele frequency greater than expected for BARD1-related disease, and no maximum-credible-frequency calculation with disease prevalence, penetrance, and allelic heterogeneity inputs is available to justify a different threshold.
Allele frequency is greater than expected for the disorder.
ClinVar contains no exact-variant expert-panel classification: the audit reports zero expert-panel submissions. The available Likely benign assertions are from ordinary clinical laboratories, and the record is conflicting with Uncertain significance submissions. Under the requested generic rule, these non-expert assertions cannot trigger BP6, so BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-level evidence establishes that NM_000465.4:c.842C>T arose de novo. The available literature does not provide a proband-level report of this exact variant, confirmed maternity and paternity, or a documented absence of family history; therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No variant-specific validated in vitro or in vivo functional assay was identified for BARD1 NM_000465.4:c.842C>T (NP_000456.2:p.(Pro281Leu)). The reviewed literature either did not mention the exact variant, reported a different BARD1 coding notation with the same protein substitution without functional testing, or provided only general variant-classification guidance. Therefore, the evidence is insufficient to assess PS3 or calibrate its strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
No case-control enrichment dataset for the exact variant NM_000465.4:c.842C>T (BARD1 p.Pro281Leu) was identified. The reviewed Rwanda paper reports a different BARD1 notation, c.421C>T, despite the same protein change, and the Saudi paper mentions BARD1 only among genes with reported SNPs; neither provides exact-variant affected/control counts. The literature_pass PS4 candidates were checked: the available extracts for PMID:32959997, PMID:32994724, and PMID:25394175 do not support exact-variant case-control evidence, while PMID:25085752 is a general BRCA1/2 reclassification algorithm paper without available exact-variant case-control data. Therefore an OR and 95% CI cannot be computed, and PS4 is not assessed rather than met or not_met.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... 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.
No VCEP covers BARD1, vcep_materials.json has no BARD1 domain-table entry, and the supplied hotspot evidence reports no statistically significant hotspot for BARD1 P281. The available evidence does not establish whether Pro281 lies in a generic critical, well-established functional domain without benign variation, so PM1 cannot be adjudicated under generic ACMG/AMP.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM3 requires a recessive disorder context and evidence that the assessed variant is in trans with a pathogenic variant. The available case evidence does not establish the inheritance mode for the relevant BARD1 disorder, does not identify a pathogenic second allele, and does not provide parental or offspring testing to determine phase. The ClinVar record and literature evidence do not document an affected proband with confirmed trans phase for NM_000465.4:c.842C>T (NP_000456.2:p.(Pro281Leu)). Therefore PM3 cannot be assessed.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The available PM5 candidate file contains zero same-residue candidates and explicitly states that classic same-residue PM5 semantics could not be confirmed safely. No previously pathogenic alternate missense change at BARD1 Pro281 is documented in the supplied evidence, but the search artifact is not sufficient to establish a complete negative result.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
No case-level evidence establishes that NM_000465.4:c.842C>T was assumed de novo. The available literature does not provide an exact-variant proband report with parental testing absent or unconfirmed; therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No exact-variant family data show co-segregation with disease in affected relatives. The available literature does not document NM_000465.4:c.842C>T in affected family members, unaffected relatives, or informative meioses; therefore PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The supplied case materials do not provide a gene-level assessment demonstrating both a low rate of benign missense variation in BARD1 and that missense variants are a common disease mechanism. The low population frequency of this individual variant and its ClinVar classifications do not establish either PP2 requirement.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The available case evidence does not provide a defined patient phenotype or family history for this case that is highly specific for a single-gene BARD1 disorder. The literature reports cancer cohorts, but the exact queried variant is not established in those reports, and general breast or colorectal cancer is not itself a highly specific phenotype for a single genetic etiology. Therefore PP4 cannot be assessed from the supplied evidence.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. gnomAD reports zero homozygotes, but its aggregate heterozygote observations do not document that a specific carrier was a healthy adult, establish adult age, or establish absence of disease. The required early-age full-penetrance condition and a directly documented healthy adult observation are not available.
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 variant-specific validated in vitro or in vivo functional assay was identified for BARD1 NM_000465.4:c.842C>T (NP_000456.2:p.(Pro281Leu)). The reviewed literature either did not mention the exact variant, reported a different BARD1 coding notation with the same protein substitution without functional testing, or provided only general variant-classification guidance. Therefore, the evidence is insufficient to assess BS3 or calibrate its strength.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No exact-variant family data identify affected relatives who lack NM_000465.4:c.842C>T. The available literature does not provide an informative family with genotype-negative affected members, so lack of segregation cannot be assessed.
Lack of segregation in affected members of a family.
The supplied materials do not establish that BARD1 disease is caused primarily by truncating variants. Evidence that BARD1 loss of function can occur in disease contexts is not sufficient to show that missense variants are generally outside the disease mechanism, so BP1 cannot be applied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires observation of the assessed variant either in trans with a pathogenic variant in a fully penetrant dominant gene/disorder or in cis with a pathogenic variant in any inheritance pattern. The available case evidence does not document a pathogenic partner, affected-proband allelic observation, or confirmed cis/trans phase for NM_000465.4:c.842C>T (NP_000456.2:p.(Pro281Leu)). Therefore 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.
No evidence in the supplied case materials shows the exact BARD1 c.842C>T variant in a case with an alternate molecular basis for disease. The available cancer-cohort papers do not establish the exact variant or an alternate molecular diagnosis for a case carrying it. BP5 therefore cannot be assessed.
Variant found in a case with an alternate molecular basis for disease.
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.842C>T in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Pro281Leu). 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. No VCEP criteria specification covers PVS1 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_null_variant_class
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.842C>T in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Pro281Leu). 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
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.842C>T in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Pro281Leu). 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
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.842C>T in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Pro281Leu). 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 |
|---|
| African/African American52 / 74,758 | 0.0007 |
| Remaining individuals1 / 62,322 | 1.6e-05 |
| South Asian1 / 90,474 | 1.1e-05 |
| African/African American15 / 24,696 | 0.00061 |
This variant is present in gnomAD v4.1 (AF= 3.35149e-05; MAF= 0.00335%, 54/1611222 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000695578; MAF= 0.06956%, 52/74758 alleles, homozygotes = 0); grpmax FAF= 0.00054438.
This variant is present in gnomAD v2.1 (AF= 5.36538e-05; MAF= 0.00537%, 15/279570 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000607386; MAF= 0.06074%, 15/24696 alleles, homozygotes = 0); grpmax FAF= 0.00029888.
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; the SpliceAI score is not used for missense BP4. REVEL is 0.066, which is at or below the supplied generic BP4 supporting threshold of <=0.29, supporting BP4 at supporting strength. The BayesDel score is not used because no generic ACMG-strength calibration is established for BayesDel.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The variant is a missense substitution, so the governing generic rule selects the REVEL path only; splice prediction is not used for missense PP3/BP4. REVEL is 0.066, below the supplied generic PP3 supporting threshold of >=0.644, and therefore does not support PP3 at any strength. BayesDel is not usable because no generic ACMG-strength calibration is established for it.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent
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.842C>T in BARD1 is a missense substitution predicted to produce NP_000456.2:p.(Pro281Leu). 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 = 0.02). REVEL score = 0.066. BayesDel score = -0.379677.
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.
The impact of a missense change depends on criteria such as the evolutionary conservation of an amino acid or nucleotide, the location and context within the protein sequence, and the biochemical consequence of the amino acid substitution.
Computational (In Silico) Predictive Programs
BARD1 NM_000465.4 c.421C>T p.(Pro281Leu) missense NA 1 NA NA
Table 3, Variants of unknown significance (VUS)
Along with the new mutations shown above, we also observed already reported SNPs in genes (n = 82), such as FANCB, BARD1, HNF1A, PALLD, FANCA, FANCD2, MUTYH, WRN, APC, POLD1, MET, CYLD, RAD50, ATM, BRCA1, MSH6, POLE, RSPO1, BRCA2, ERCC2, MLH1, MYH8, TSC2, ALK, BUB1, MLH3, MSH2, PTCH1, RECQL4, SDHA, ATR, CBL, FLCN, KDR, MITF, PDGFRB, RHBDF2, SLX4 , AXIN2, BMPR1A, DICER1, EGFR, EXT2, FANCI, GPC3, PMS2, PTCH2, RAD51D, RUNX1, VHL, WAS, BLM, BRIP1, CDH1, CDKN1B, CHEK2, CTHRC1, EPCAM, ERCC3, FANCF, FANCG, FANCL, FANCM, FH, HNF1B, KLLN, LIG4, MEN1, MRE11A, MSR1, NBN, NF2, NTRK1, PALB2, PPM1D, PRKAR1A, PTPN11, RB1, RET, RNF168, SETBP1, SMAD4, STK11, TP53, WT1, and XPC (Supplementary Tables 1 and 2). Few of these SNPs were in the exonic region.
Results, section 3.2, paragraph beginning “Along with the new mutations shown above…”
We developed a statistical variant reclassification tool based on the pre
Abstract snippet in literature_pass.json
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= 3.35149e-05; MAF= 0.00335%, 54/1611222 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000695578; MAF= 0.06956%, 52/74758 alleles, homozygotes = 0); grpmax FAF= 0.00054438.
This variant is present in gnomAD v2.1 (AF= 5.36538e-05; MAF= 0.00537%, 15/279570 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000607386; MAF= 0.06074%, 15/24696 alleles, homozygotes = 0); grpmax FAF= 0.00029888.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Uncertain significance (6 clinical laboratories). (ClinVarID = 185922)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.066. BayesDel score = -0.379677.
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.