NM_000465.4:c.568G>A

BARD1 · NP_000456.2:p.(Asp190Asn) · NM_000465.4

GRCh37: chr2:215646030 C>T · GRCh38: chr2:214781306 C>T

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Asp190Asn)

gnomAD AF

0.00012163079592462365 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 is not applicable. This is a missense variant (NM_000465.4:c.568G>A, p.Asp190Asn) in BARD1 exon 4. PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). The pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic missense variant with the same amino acid change (p.Asp190) has been established in ClinVar or the literature. PS1 requires a previously classified pathogenic variant at the same residue with the same amino acid change.	clinvar pm5_candidates
PS2	Not met	No de novo data are available for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed.
PS3	Not met	No variant-specific functional data exist for p.Asp190Asn. The most comprehensive functional study of BARD1 missense variants (Adamovich et al. 2019, PMID:30925164) tested 76 variants in an HDR assay but did not include D190N. The variant resides in the linker region between the RING and ankyrin repeat domains, where all 22 tested variants were HDR-functional. However, PS3 requires variant-level or systematic range data, and domain-level inference from sparse testing does not satisfy PS3.	PMID:30925164
PS4	Not met	No case-control data are available demonstrating enrichment of this variant in affected individuals versus controls. PS4 requires statistically significant enrichment in affected individuals.
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (12 laboratories) and Likely benign (5 laboratories), with review status 'criteria provided, single submitter' (1-star). No expert panel has classified this variant as pathogenic.	clinvar
PM1	Not met	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. Per Adamovich et al. 2019 (PMID:30925164), all 22 missense variants tested in this inter-domain region were HDR-functional, indicating no critical DNA repair function associated with this region. Residue-specific hotspot analysis at cancerhotspots.org is also negative.	PMID:30925164 oncokb
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same residue (p.Asp190) with a different amino acid change has been established. The PM5 candidate search found zero same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PM6	Not met	No de novo data are available for this variant. PM6 requires a de novo observation with both maternity and paternity confirmed, without confirmation of the variant as a de novo event.
PP1	Not met	No cosegregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not met	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. PP2 is reserved for genes where missense variants are NOT a common mechanism of disease (low rate of benign missense variation). BARD1 does not meet this criterion.	PMID:30925164
PP3	Not met	Multiple lines of computational evidence support a benign interpretation. REVEL score is 0.053 (strongly benign; threshold for pathogenic is typically >0.5). BayesDel score is -0.567 (benign; negative scores predict benign). SpliceAI max delta is 0.11 (no predicted splicing impact). No in silico tool predicts a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype or family history data are available for this variant. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	ClinVar classification is Uncertain significance (12 clinical laboratories) and Likely benign (5 clinical laboratories), with review status 'criteria provided, single submitter' (1-star). No expert panel (3-star) has evaluated this variant. PP5 requires a 3-star expert panel classification as pathogenic to be applied at supporting level per established framework rules.	clinvar
BA1	Not met	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).	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals at significant frequency. gnomAD counts (17 in v2.1, 196 in v4.1) are low and represent population cohorts, not specifically documented healthy controls.
BS3	Not met	No variant-specific well-established functional studies demonstrate no damaging effect. While the region between the RING and ankyrin domains showed HDR proficiency for all 22 tested variants (PMID:30925164), this is domain-level inference, not variant-level functional data. BS3 requires well-established functional studies showing no damaging effect for the specific variant.	PMID:30925164
BS4	Not met	No segregation data are available for this variant. BS4 requires lack of segregation with disease in affected family members.
BP1	Not met	BARD1 is a gene for which both missense and truncating variants are known to cause disease. Multiple missense variants in the RING domain (L44R, C53W, C71Y) and BRCT domain (T598I, S660R, G698D, P707S, G753D) have been shown to be HDR-deficient and are considered pathogenic (PMID:30925164). BP1 applies only when primarily truncating variants cause disease.	PMID:30925164
BP2	Not met	No data are available regarding observation of this variant in trans with a pathogenic variant for BARD1, which is associated with autosomal dominant inheritance. BP2 requires observation in trans with a pathogenic variant in a fully penetrant dominant disorder.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data are available identifying an alternate molecular basis for disease in a case carrying this variant. BP5 requires that the variant is found in a case with an established alternative genetic cause of the phenotype.
BP6	Not met	While 5 clinical laboratories have classified this variant as Likely benign in ClinVar, the overall review status is 'criteria provided, single submitter' (1-star). BP6 requires a 3-star expert panel classification as benign to be applied at supporting level per established framework rules.	clinvar
BP7	N/A	BP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_000465.4:c.568G>A is a missense variant (p.Asp190Asn), not a synonymous variant.

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