NM_000465.4:c.1409A>G (p.Asn470Ser) is a missense variant in exon 6 of BARD1. This variant is present at extremely low frequency in gnomAD (v2.1: AF = 0.0113%, 32/282,604 alleles; v4.1: AF = 0.0088%, 142/1,613,858 alleles; 0 homozygotes), meeting PM2 at supporting level.1 Multiple in silico tools predict a benign effect: REVEL score 0.17, BayesDel score -0.585, and SpliceAI delta score 0.00, meeting BP4 at supporting level.2 The variant was reported as a putative germline mutation in 1 of 60 Japanese familial breast cancer patients and absent from 152 controls (Ishitobi et al., 2003), but this single observation is insufficient for PS4.3 No variant-specific functional data exist; the functional study by Toh et al. (2019) characterized BARD1 germline variants but did not include N470S.4 BARD1 is a recognized hereditary breast cancer susceptibility gene with a loss-of-function disease mechanism, consistent with tumor suppressor biology.5 In ClinVar, this variant is classified as Uncertain significance (review status: criteria provided, single submitter). Multiple clinical laboratories have submitted conflicting classifications: 8 laboratories as VUS, 5 as Likely benign, and 1 as Benign.6 The variant lies within the ankyrin repeat domain, a characterized protein-protein interaction domain, but the residue is not within a statistically significant mutational hotspot.7
BARD1
Final classification
VUS
BARD1 c.1409A>G · p.Asn470Ser
BARD1
NM_000465.4:c.1409A>G (p.Asn470Ser) is a missense variant in exon 6 of BARD1.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BARD1 c.1409A>G
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
Gene diagram
· NM_000465.4 · variants mapped to exon structure
BARD1
NM_000465.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases. In gnomAD v2.1, it is observed in 32 of 282,604 alleles (AF = 0.0113%; 0 homozygotes). In gnomAD v4.1, it is observed in 142 of 1,613,858 alleles (AF = 0.0088%; 0 homozygotes). The highest subpopulation frequency is in the European (Finnish) population at 0.0478% (v2.1). All frequencies are below the 0.1% threshold for PM2 under generic ACMG criteria.
gnomAD v2.1: AF = 0.0113% (32/282604 alleles0 hom).
✓
BP4
supporting
Benign
Multiple lines of computational evidence predict a benign effect for this variant. REVEL score is 0.17 (well below pathogenic thresholds), BayesDel score is -0.585 (consistent with benign), and SpliceAI predicts no splicing impact (max delta score = 0.00). The concordance of multiple in silico predictors supports a lack of functional impact.
REVEL: 0.17 (benign range).BayesDel: -0.585 (benign range).SpliceAI: max delta = 0.00 (no predicted splicing alteration).
Assessed · not applied
Pathogenic
PS1
No prior report of a different nucleotide change at codon 470 resulting in the same amino acid substitution (p.Asn470Ser) that has been classified as pathogenic.
PS2
No de novo observation has been reported for NM_000465.4:c.1409A>G.
PS3
No variant-specific functional data exist for NM_000465.4:c.1409A>G (p.Asn470Ser).
PS4
The variant was observed in 1 of 60 familial breast cancer patients and absent from 152 controls (PMID:14550946), but this single observation does not provide statistically significant enrichment.
PM1
The variant (p.Asn470Ser) lies within the ankyrin repeat domain of BARD1 (residues ~420-555), a characterized functional domain mediating protein-protein interactions.
PM5
No pathogenic missense variant at the same codon (Asn470) was identified in ClinVar.
PM6
No de novo observation has been reported for NM_000465.4:c.1409A>G.
PP1
No co-segregation data are available.
PP2
No gene-level constraint data (e.g., Missense Z-score, gnomAD constraint metrics) are available in the evidence summary to assess whether BARD1 has a low rate of benign missense variation.
PP3
All in silico tools predict a benign effect.
PP4
Insufficient clinical phenotype data are available to determine whether the patient's presentation is highly specific for BARD1-related disease.
PP5
ClinVar aggregate classification is Uncertain significance (review status: criteria provided, single submitter; 1-star).
Benign
BA1
The allele frequency in gnomAD is 0.0113% (v2.1) and 0.0088% (v4.1), both far below the 1% threshold for BA1.
BS1
The allele frequency in gnomAD is 0.0113% (v2.1) and 0.0088% (v4.1), below the 0.3% threshold for BS1.
BS2
No data are available on observation of this variant in a healthy adult at an age when full penetrance of BARD1-related disease would be expected.
BS3
No well-established functional studies have demonstrated that NM_000465.4:c.1409A>G (p.Asn470Ser) has no deleterious effect.
BS4
No non-segregation data are available for this variant.
BP1
BP1 applies to missense variants in genes where the primary disease mechanism involves truncating variants.
BP2
No observation of this variant in trans with a known pathogenic BARD1 variant has been reported.
BP5
No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6
Although 6 of 17 ClinVar submissions classify this variant as Likely benign (n=5) or Benign (n=1), the aggregate ClinVar classification remains Uncertain significance with a 1-star review status.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.79879e-05; MAF= 0.00880%, 142/1613858 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000656353; MAF= 0.06564%, 42/63990 alleles, homozygotes = 0); grpmax FAF= 0.0001336.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000113233; MAF= 0.01132%, 32/282604 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000477897; MAF= 0.04779%, 12/25110 alleles, homozygotes = 0); grpmax FAF= 8.821e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0088%
· 142 / 1,613,858
0 hom · FAF 0.013%
0 hom · FAF 0.013%
European (Finnish) 42 / 63,990 |
0.066% |
Middle Eastern 3 / 6,082 |
0.049% |
Admixed American 8 / 59,986 |
0.013% |
Remaining individuals 5 / 62,474 |
0.008% |
European (non-Finnish) 82 / 1,179,948 |
0.0069% |
African/African American 1 / 74,900 |
0.0013% |
South Asian 1 / 91,084 |
0.0011% |
+ 3 not observed (Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.011%
· 32 / 282,604
0 hom · FAF 0.0088%
0 hom · FAF 0.0088%
European (Finnish) 12 / 25,110 |
0.048% |
Remaining individuals 2 / 7,208 |
0.028% |
Admixed American 4 / 35,374 |
0.011% |
European (non-Finnish) 13 / 129,016 |
0.01% |
South Asian 1 / 30,610 |
0.0033% |
+ 3 not observed (African/African American, Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory). (ClinVarID = 141739)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.17. BayesDel score = -0.584707.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
18480049 ↗
Crystal structure of the BARD1 ankyrin repeat domain and its functional consequences.
CLINVAR
19584272 ↗
Modification of ovarian cancer risk by BRCA1/2-interacting genes in a multicenter cohort of BRCA1/2 mutation carriers.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
30374176 ↗
Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.
CLINVAR
36187937 ↗
BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR