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LYFE SCIENCES
Project: HERA
NM_000465.4:c.764A>G
p.Asn255Ser  ·  BARD1
ACMG/AMP
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Classification rationale
1

The BARD1 c.764A>G (p.Asn255Ser) variant has been reported in ClinVar predominantly as uncertain significance, with 11 uncertain significance submissions and 1 likely benign submission.

clinvar ↗
2

This variant is present at low frequency in population databases, with a total allele frequency of 0.00316% in gnomAD v2.1 and 0.00228% in gnomAD v4.1; the highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which remains below the 0.1% rarity threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

Available computational evidence is consistent with no significant functional impact, with SpliceAI predicting no significant splice effect (maximum delta score 0.04), REVEL 0.241, and BayesDel -0.546443.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.16131e-05; MAF= 0.00316%, 8/253060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000327976; MAF= 0.03280%, 8/24392 alleles, homozygotes = 0); grpmax FAF= 0.00016648.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.27556e-05; MAF= 0.00228%, 36/1582026 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000422366; MAF= 0.04224%, 31/73396 alleles, homozygotes = 0); grpmax FAF= 0.00030571.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.241. BayesDel score = -0.546443.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueN255
Hotspots ↗