Classification rationale

PM2 BP4 VUS

BARD1 c.764A>G

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.¹ 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.² 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 -0.546443.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

Gene diagram · NM_000465.4 · variants mapped to exon structure

BARD1 NM_000465.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This 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.

v2.1

This 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.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0023% · 36 / 1,582,026
0 hom · FAF 0.031%

African/African American 31 / 73,396	0.042%
Admixed American 4 / 54,192	0.0074%
Remaining individuals 1 / 60,992	0.0016%

+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.0032% · 8 / 253,060
0 hom · FAF 0.017%

African/African American

8 / 24,392

0.033%

+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (1 clinical laboratory).

ClinVar ↗

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 ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots