NM_000465.4:c.1409A>G

BARD1 · NP_000456.2:p.(Asn470Ser) · NM_000465.4

GRCh37: chr2:215632365 T>C · GRCh38: chr2:214767641 T>C

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.(Asn470Ser)

gnomAD AF

8.798791467402956e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000465.4:c.1409A>G (p.Asn470Ser) is a missense variant in exon 6 of BARD1.

This variant is present at extremely low frequency in gnomAD (v2.1: AF = 0.0113%, 32/282,604 alleles; v4.1: AF = 0.0088%, 142/1,613,858 alleles; 0 homozygotes), meeting PM2 at supporting level.

Multiple in silico tools predict a benign effect: REVEL score 0.17, BayesDel score -0.585, and SpliceAI delta score 0.00, meeting BP4 at supporting level.

The variant was reported as a putative germline mutation in 1 of 60 Japanese familial breast cancer patients and absent from 152 controls (Ishitobi et al., 2003), but this single observation is insufficient for PS4.

No variant-specific functional data exist; the functional study by Toh et al. (2019) characterized BARD1 germline variants but did not include N470S.

BARD1 is a recognized hereditary breast cancer susceptibility gene with a loss-of-function disease mechanism, consistent with tumor suppressor biology.

In ClinVar, this variant is classified as Uncertain significance (review status: criteria provided, single submitter). Multiple clinical laboratories have submitted conflicting classifications: 8 laboratories as VUS, 5 as Likely benign, and 1 as Benign.

The variant lies within the ankyrin repeat domain, a characterized protein-protein interaction domain, but the residue is not within a statistically significant mutational hotspot.

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	NM_000465.4:c.1409A>G (p.Asn470Ser) is a missense variant in exon 6 of BARD1. It does not fall into the default generic PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Generic PVS1 framework is not applicable for this variant type.	pvs1_variant_assessment
PS1	Not met	No prior report of a different nucleotide change at codon 470 resulting in the same amino acid substitution (p.Asn470Ser) that has been classified as pathogenic.	clinvar pm5_candidates
PS2	Not met	No de novo observation has been reported for NM_000465.4:c.1409A>G.
PS3	Not met	No variant-specific functional data exist for NM_000465.4:c.1409A>G (p.Asn470Ser). The functional study by Toh et al. (PMID:31371347) characterized other BARD1 germline variants but did not include N470S. The variant was listed in a pediatric oncology cohort table in PMID:36187937 but was not functionally tested.	PMID:31371347 PMID:36187937
PS4	Not met	The variant was observed in 1 of 60 familial breast cancer patients and absent from 152 controls (PMID:14550946), but this single observation does not provide statistically significant enrichment. No case-control study with sufficient power has been conducted.	PMID:14550946
PS5	Not met	This variant is not established as pathogenic by any reputable source. The ClinVar aggregate classification is Uncertain significance with a single-submitter review status.	clinvar
PM1	Not met	The variant (p.Asn470Ser) lies within the ankyrin repeat domain of BARD1 (residues ~420-555), a characterized functional domain mediating protein-protein interactions. However, the residue is not located in a statistically significant mutational hotspot (cancerhotspots.org: residue not significant), and no cluster of pathogenic missense variants has been established specifically within the ankyrin repeat domain of BARD1. The ankyrin repeat domain crystal structure (PMID:18480049) confirms it is a structured domain, but domain-level characterization alone is insufficient for PM1 without evidence of pathogenic missense enrichment.	PMID:16633366 PMID:18480049
PM2	Met	This variant is present at extremely low frequency in population databases. In gnomAD v2.1, it is observed in 32 of 282,604 alleles (AF = 0.0113%; 0 homozygotes). In gnomAD v4.1, it is observed in 142 of 1,613,858 alleles (AF = 0.0088%; 0 homozygotes). The highest subpopulation frequency is in the European (Finnish) population at 0.0478% (v2.1). All frequencies are below the 0.1% threshold for PM2 under generic ACMG criteria.	gnomad_v2 gnomad_v4 PMID:19584272
PM5	Not met	No pathogenic missense variant at the same codon (Asn470) was identified in ClinVar. The PM5 candidate harvest did not identify any same-residue pathogenic comparators.	pm5_candidates
PM6	Not met	No de novo observation has been reported for NM_000465.4:c.1409A>G.
PP1	Not met	No co-segregation data are available. The proband reported in PMID:14550946 had affected family members (mother and maternal aunt with breast cancer), but DNA from other family members was unavailable, preventing segregation analysis.	PMID:14550946
PP2	Not met	No gene-level constraint data (e.g., Missense Z-score, gnomAD constraint metrics) are available in the evidence summary to assess whether BARD1 has a low rate of benign missense variation. BARD1 is a known tumor suppressor, but PP2 requires quantitative evidence of missense constraint.
PP3	Not met	All in silico tools predict a benign effect. REVEL score is 0.17 (below the typical 0.3-0.5 pathogenic threshold), BayesDel score is -0.585 (negative, consistent with benign), and SpliceAI delta score is 0.0 (no splicing impact). Multiple lines of computational evidence support no deleterious effect.	revel bayesdel spliceai
PP4	Not met	Insufficient clinical phenotype data are available to determine whether the patient's presentation is highly specific for BARD1-related disease.
PP5	Not met	ClinVar aggregate classification is Uncertain significance (review status: criteria provided, single submitter; 1-star). No 3-star expert panel has classified this variant. Under the established rules, PP5 requires a 3-star expert panel for supporting-level application. Additionally, 6 of 17 submissions classify the variant as Likely benign or Benign.	clinvar
BA1	Not met	The allele frequency in gnomAD is 0.0113% (v2.1) and 0.0088% (v4.1), both far below the 1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD is 0.0113% (v2.1) and 0.0088% (v4.1), below the 0.3% threshold for BS1. The highest subpopulation frequency is 0.0478% (Finnish, v2.1), still well below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on observation of this variant in a healthy adult at an age when full penetrance of BARD1-related disease would be expected.
BS3	Not met	No well-established functional studies have demonstrated that NM_000465.4:c.1409A>G (p.Asn470Ser) has no deleterious effect. The only functional study of BARD1 germline variants (PMID:31371347) did not include N470S among the variants tested.	PMID:31371347
BS4	Not met	No non-segregation data are available for this variant.
BP1	Not met	BP1 applies to missense variants in genes where the primary disease mechanism involves truncating variants. BARD1-associated disease involves both truncating and missense pathogenic variants (e.g., RING domain missense variants that disrupt BRCA1 binding), so BARD1 is not a gene where only truncating variants cause disease.	PMID:16633366
BP2	Not met	No observation of this variant in trans with a known pathogenic BARD1 variant has been reported.
BP4	Met	Multiple lines of computational evidence predict a benign effect for this variant. REVEL score is 0.17 (well below pathogenic thresholds), BayesDel score is -0.585 (consistent with benign), and SpliceAI predicts no splicing impact (max delta score = 0.00). The concordance of multiple in silico predictors supports a lack of functional impact.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in a case harboring this variant.
BP6	Not met	Although 6 of 17 ClinVar submissions classify this variant as Likely benign (n=5) or Benign (n=1), the aggregate ClinVar classification remains Uncertain significance with a 1-star review status. Under the established rules, BP6 requires a 3-star expert panel classification for application at supporting level. No expert panel has reviewed this variant.	clinvar
BP7	N/A	NM_000465.4:c.1409A>G is a missense variant resulting in p.Asn470Ser. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant; BARD1-related disease is autosomal dominant.
PM4	N/A	PM4 applies to non-frameshift insertions/deletions or stop-loss variants; this is a single nucleotide substitution.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.