Classification rationale

PM2 BP4 VUS

BARD1 c.568G>A

NM_000465.4:c.568G>A (p.Asp190Asn) is a missense variant in exon 4 of BARD1. This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00607% (17/280,222 alleles) and gnomAD v4.1 AF = 0.01216% (196/1,611,434 alleles), meeting PM2 at supporting strength.¹ Multiple lines of computational evidence support a benign interpretation: REVEL score 0.053, BayesDel score -0.567, and SpliceAI max delta 0.11, meeting BP4 at supporting strength.² No variant-specific functional data exist. Adamovich et al. 2019 (PMID:30925164) tested 76 BARD1 missense variants in an HDR assay but did not include p.Asp190Asn. All 22 variants in the linker region between the RING and ankyrin domains were found to be HDR-functional.³ This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories) and Likely benign (5 clinical laboratories), with review status 'criteria provided, single submitter' (1-star). No expert panel has evaluated this variant.⁴ PVS1 is not applicable as this is a missense variant. PS1-PS5, PM1, PM5-PM6, PP1-PP5, BA1, BS1-BS4, BP1-BP2, BP5-BP6 are not met. BP7 is not applicable. The net evidence balance is PM2 (supporting pathogenic) + BP4 (supporting benign), resulting in a classification of Variant of Uncertain Significance.

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 PMID:30925164 ↗

4 clinvar ↗

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. gnomAD v2.1: 17/280,222 alleles (AF = 0.00607%); gnomAD v4.1: 196/1,611,434 alleles (AF = 0.01216%). Both are well below the 0.1% threshold for PM2 supporting. No homozygotes observed. Highest subpopulation frequency is European (non-Finnish): 0.0125% (v2.1) and 0.0155% (v4.1).

gnomAD v2.1 AF = 0.00607% (<0.1%)v4.1 AF = 0.01216% (<0.1%)absent from gnomAD-Canada.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence support a benign interpretation. REVEL score is 0.053 (strongly predicts benign), BayesDel score is -0.567 (predicts benign), and SpliceAI max delta is 0.11 (no predicted splicing impact). All available in silico tools agree on a lack of deleterious effect.

REVEL 0.053 (benign)BayesDel -0.567 (benign)SpliceAI 0.11 (no splice impact). All computational tools predict no deleterious effect.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No known pathogenic missense variant with the same amino acid change (p.Asp190) has been established in ClinVar or the literature.

PS2 No de novo data are available for this variant.

PS3 No variant-specific functional data exist for p.Asp190Asn.

PS4 No case-control data are available demonstrating enrichment of this variant in affected individuals versus controls.

PM1 p.Asp190 is located in the linker region between the BARD1 RING domain (aa ~46-90) and the ankyrin repeat domain (aa ~427+), not within a characterized critical functional domain.

PM5 No pathogenic missense variant at the same residue (p.Asp190) with a different amino acid change has been established.

PM6 No de novo data are available for this variant.

PP1 No cosegregation data are available for this variant.

PP2 BARD1 has known pathogenic missense variants (e.g., in RING domain: L44R, C53W, C71Y; in BRCT domain: T598I, S660R, G698D, P707S, G753D per PMID:30925164), indicating that missense variation is an established disease mechanism for this gene.

PP3 Multiple lines of computational evidence support a benign interpretation.

PP4 No patient-specific phenotype or family history data are available for this variant.

PP5 ClinVar classification is Uncertain significance (12 clinical laboratories) and Likely benign (5 clinical laboratories), with review status 'criteria provided, single submitter' (1-star).

Benign

BA1 The maximum population allele frequency of this variant is 0.0155% (gnomAD v4.1 European non-Finnish), far below the 1% threshold required for BA1 (stand-alone benign).

BS1 The maximum population allele frequency of this variant is 0.0155% (gnomAD v4.1 European non-Finnish), below the 0.3% threshold required for BS1 (strong benign) under the generic ACMG framework.

BS2 No data are available regarding observation of this variant in healthy adult individuals at significant frequency.

BS3 No variant-specific well-established functional studies demonstrate no damaging effect.

BS4 No segregation data are available for this variant.

BP1 BARD1 is a gene for which both missense and truncating variants are known to cause disease.

BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for BARD1, which is associated with autosomal dominant inheritance.

BP5 No data are available identifying an alternate molecular basis for disease in a case carrying this variant.

BP6 While 5 clinical laboratories have classified this variant as Likely benign in ClinVar, the overall review status is 'criteria provided, single submitter' (1-star).

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000121631; MAF= 0.01216%, 196/1611434 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000155152; MAF= 0.01552%, 183/1179486 alleles, homozygotes = 0); grpmax FAF= 0.00013673.

v2.1

This variant is present in gnomAD v2.1 (AF= 6.06662e-05; MAF= 0.00607%, 17/280222 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000124789; MAF= 0.01248%, 16/128216 alleles, homozygotes = 0); grpmax FAF= 8.165e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0003801042571676803, 7/18416 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.012% · 196 / 1,611,434
0 hom · FAF 0.014%

European (non-Finnish) 183 / 1,179,486	0.016%
Admixed American 7 / 59,660	0.012%
African/African American 5 / 74,772	0.0067%
Remaining individuals 1 / 62,390	0.0016%

+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0061% · 17 / 280,222
0 hom · FAF 0.0082%

European (non-Finnish) 16 / 128,216	0.012%
Admixed American 1 / 35,040	0.0029%

+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

0.038% · 7 / 18,416
0 hom · FAF 0.028%

European (non-Finnish)

7 / 11,738

0.06%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 142184)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11). REVEL score = 0.053. BayesDel score = -0.567143.

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 previously been reported in somatic cancers (COSMIC; COSV105028599, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 9 PMIDs not cited in assessment

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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

27978560 ↗ Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. CLINVAR

28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR

30925164 ↗ Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity. CLINVAR

34326862 ↗ Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

24432435 ↗ PMID 24432435 CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR