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

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

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

BARD1 NM_000465.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

This variant is present at low frequency in gnomAD and remains below the non-VCEP rarity threshold of 0.1%. 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 is below the 0.1% threshold and supports population rarity.

gnomAD v2.1 total AF 0.00316%highest subpopulation AF 0.03280%gnomAD v4.1 total AF 0.00228%

gnomad_v2 ↗gnomad_v4 ↗

BP4 supporting review Benign

Multiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together support BP4.

SpliceAI max delta score 0.04REVEL score 0.241BayesDel score -0.546443

spliceai ↗

Assessed · not applied · 4 not met · 15 not assessed

Pathogenic

PS1 No confirmed pathogenic variant producing the same amino acid change, p.Asn255Ser, was identified in the available evidence.

PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant.

PS3 No well-established functional study demonstrating a damaging effect of this exact variant was identified in the available evidence.

PS4 This variant has been reported in ClinVar, but no case-control enrichment, odds ratio, or exact affected-carrier count sufficient for PS4 was identified.

PM1 This variant does not lie in a statistically significant hotspot, and no established critical functional domain with this exact residue was identified in the available evidence.

PM5 No different pathogenic missense change at the same codon was identified in the available evidence.

PM6 No assumed or unconfirmed de novo occurrence was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish that pathogenic missense variation is a sufficiently common disease mechanism in BARD1 to support PP2 for this variant.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No phenotype or family-history information specific enough to BARD1-related disease was identified to support PP4.

Benign

BA1 Population frequency does not reach the benign stand-alone threshold.

BS1 Population frequency is below the benign strong threshold.

BS2 No evidence was identified showing this variant in a number of well-phenotyped unaffected individuals sufficient for BS2.

BS3 No well-established functional study demonstrating normal or near-normal effect for this exact variant was identified.

BS4 No lack-of-segregation data were identified for this variant.

BP1 Although loss of function is supported as a disease mechanism in BARD1, the available evidence does not establish that pathogenic missense variation is sufficiently uncommon to apply BP1 to this missense variant.

BP2 No co-occurrence data in trans with a pathogenic variant, or in cis in a way that would support BP2, were identified for this variant.

BP5 No alternate molecular explanation for the observed disease in an affected individual was identified in the available evidence.

N/A · 7 PVS1 · PM3 · PM4 · PP5 · BP3 · BP6 · BP7

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

Check your email

Reset your password

Enter an access code

Your allowance