Variant classification summary

NM_000465.4:c.1788del

BARD1 · NP_000456.2:p.(Lys596AsnfsTer9) · NM_000465.4

GRCh37: chr2:215610467 AT>A · GRCh38: chr2:214745743 AT>A

Gene: BARD1 Transcript: NM_000465.4

Final call

Pathogenic

PVS1 very strong PM2 moderate PP5 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Lys596AsnfsTer9)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000465.4:c.1788del (p.Lys596AsnfsTer9) is a frameshift deletion in exon 8 of the BARD1 gene, predicted to trigger nonsense-mediated decay and remove the C-terminal BRCT domains essential for homology-directed DNA repair and tumor suppression.

2

BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility, supported by multiple publications identifying deleterious truncating germline BARD1 mutations in affected families.

3

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, indicating it is extremely rare in the general population.

4

Three independent clinical laboratories in ClinVar classify this variant as Pathogenic or Likely pathogenic (ClinVar Variation ID: 801882), providing additional supporting evidence.

5

Applying generic ACMG/AMP 2015 classification rules: PVS1 (very strong) + PM2 (moderate) + PP5 (supporting) meets the pathogenic threshold of 1 Very Strong + 1 Moderate + 1 Supporting.

6

Overall classification: PATHOGENIC.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

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	Met	NM_000465.4:c.1788del is a frameshift deletion in exon 8 of 11, predicted to cause a premature termination codon (p.Lys596AsnfsTer9) at codon 604, well upstream of the last exon-exon junction, and is expected to trigger nonsense-mediated decay. BARD1 loss of function is an established mechanism for hereditary breast and ovarian cancer susceptibility. The transcript NM_000465.4 is the MANE Select transcript and is biologically relevant. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this null variant in a gene where LOF is a known disease mechanism qualifies for PVS1 at very strong strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:20077502 PMID:21344236
PS1	N/A	PS1 applies when a different nucleotide change at the same position has been established as pathogenic. This is a frameshift deletion (c.1788del), not an SNV amenable to same-position comparison under PS1 semantics.
PS2	Not met	No de novo observation was identified for NM_000465.4:c.1788del in the reviewed literature or ClinVar submissions.
PS3	Not met	No variant-specific functional data was identified for NM_000465.4:c.1788del. The OncoKB annotation of 'Likely Loss-of-function' is a curated inference, not direct experimental functional evidence. No publication was found that directly tested c.1788del or a systematically characterized range encompassing position 596 in a functional assay.
PS4	Not met	The variant is reported in ClinVar as Pathogenic/Likely pathogenic by three clinical laboratories, indicating it has been observed in affected individuals. However, no published case-control study or variant-specific case counts are available in the literature. The reviewed publications report different BARD1 variants, not c.1788del. Insufficient case data to meet PS4 threshold.	clinvar
PS5	N/A	PS5 requires a different pathogenic variant at the same codon. This is a frameshift deletion, not an SNV with established same-codon comparators. PM5 is the appropriate criterion for same-residue comparisons, but this variant type does not fit classic PM5 semantics either.
PM1	N/A	While the variant removes the functionally critical BRCT domains (residues 568-777), this domain-level evidence is already fully captured by PVS1 (null variant removing critical functional domains). Applying PM1 would constitute double-counting of the same biological consequence. No independent mutational hotspot evidence exists (cancerhotspots.org negative).	PMID:20077502
PM2	Met	NM_000465.4:c.1788del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. This satisfies the PM2 threshold for a rare variant absent from large population databases (allele frequency <0.1% under generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per directive.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. c.1788del is a frameshift deletion producing a premature stop codon, which is already addressed by PVS1. Not applicable under PM4 semantics.
PM5	N/A	PM5 requires a novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic. This is a frameshift deletion (p.Lys596AsnfsTer9), not a missense variant. PM5 is not applicable. The automated pm5_candidates pipeline confirmed this: unable to parse missense residue context.	pm5_candidates
PM6	Not met	No de novo observation was identified for NM_000465.4:c.1788del in the reviewed literature or ClinVar submissions. Assumed de novo status is not sufficient; a confirmed de novo report is required.
PP1	Not met	No cosegregation data was identified for NM_000465.4:c.1788del. The publications reviewed report segregation data for different BARD1 variants (p.Glu652fs in PMID:20077502; p.Gln564X and others in PMID:21344236), not c.1788del.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a frameshift deletion, not a missense variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.03). REVEL and BayesDel scores are unavailable because the variant is not an SNV. No in silico evidence supports a deleterious effect on splicing or protein function beyond the known consequence of the frameshift itself (already captured by PVS1).	spliceai
PP4	Not met	No specific patient phenotype or family history data is available for the individual(s) carrying NM_000465.4:c.1788del. The ClinVar submissions originate from clinical testing laboratories but do not include detailed phenotype descriptions.	clinvar
PP5	Met	NM_000465.4:c.1788del is classified as Pathogenic by two clinical laboratories and Likely pathogenic by one clinical laboratory in ClinVar (ClinVarID: 801882). While the review status is 'criteria provided, single submitter' (1-star, not expert panel), the concordant classification from three independent clinical testing laboratories provides supporting evidence for pathogenicity. The evidence used by these laboratories is partially verifiable (PM2 — absence from population databases).	clinvar
BA1	Not met	NM_000465.4:c.1788del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BA1 threshold of allele frequency >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	NM_000465.4:c.1788del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the BS1 threshold of allele frequency >0.3% in any population.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of NM_000465.4:c.1788del in healthy adults. The variant is absent from population databases, so healthy adult carrier data is not available.
BS3	Not met	No functional studies were identified that demonstrate NM_000465.4:c.1788del has no damaging effect on protein function or splicing. The frameshift nature of the variant predicts a severe loss-of-function effect, which is opposite to what BS3 requires.
BS4	Not met	No cosegregation data is available for NM_000465.4:c.1788del. BS4 requires lack of segregation in affected family members, which cannot be assessed without family studies.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant, not a missense variant.
BP2	Not met	No data on observation of NM_000465.4:c.1788del in trans with a known pathogenic BARD1 variant. BP2 cannot be assessed without phase information.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion, not an in-frame variant.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta = 0.03), but this is a single computational data point, not 'multiple lines of computational evidence' as required by BP4. Furthermore, the frameshift nature of the variant itself is inherently damaging to the protein, contradicting BP4's requirement for benign computational evidence. REVEL and BayesDel are not applicable to this variant type.	spliceai
BP5	Not met	No evidence was identified that NM_000465.4:c.1788del occurs in a case with an alternate molecular basis for disease. The ClinVar submissions report this variant in individuals with hereditary breast/ovarian cancer phenotypes, without indication of an alternative molecular cause.
BP6	Not met	ClinVar classifies NM_000465.4:c.1788del as Pathogenic/Likely pathogenic, not benign. BP6 requires a reputable source to report the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact and low nucleotide conservation. This is a frameshift deletion, not a synonymous variant.

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