NM_000465.4:c.1868G>A

BARD1 · NP_000456.2:p.(Gly623Glu) · NM_000465.4

GRCh37: chr2:215609826 C>T · GRCh38: chr2:214745102 C>T

Gene: BARD1 Transcript: NM_000465.4

Final call

VUS

PS3 moderate PM2 supporting BP4 supporting

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Gly623Glu)

gnomAD AF

2.2926797832735997e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BARD1 c.1868G>A (p.Gly623Glu) variant is a missense substitution classified as a variant of uncertain significance. Functional evidence from a homology-directed DNA repair assay demonstrates that this variant significantly reduces HDR activity (14–19% of wild-type) and disrupts BRCA1 binding, meeting PS3 at moderate strength (Lee et al., 2015).

The variant is absent or extremely rare in population databases (gnomAD v2.1 AF 0.00119%; v4.1 AF 0.00229%), meeting PM2 at supporting strength.

Multiple computational predictors suggest a benign effect: BayesDel score is 0.016 (benign-leaning), REVEL score is 0.388 (indeterminate), and SpliceAI predicts no splicing impact (max delta 0.05), meeting BP4 at supporting strength.

At the time of assessment, no CSPEC or VCEP framework exists for BARD1. The generic ACMG/AMP 2015 framework was applied. Combining PS3_moderate and PM2_supporting with BP4_supporting yields a net evidence profile of one moderate pathogenic criterion plus one supporting pathogenic criterion partially offset by one supporting benign criterion, resulting in an overall classification of Uncertain Significance.

ClinVar classifies this variant as Uncertain Significance (1-star, 8 clinical laboratories, ClinVar Variation ID 142123). The evidence from this independent adjudication is consistent with that classification.

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.1868G>A is a missense variant (p.Gly623Glu). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	N/A	No previously established pathogenic missense variant at the same amino acid position with a different nucleotide change was identified for BARD1 Gly623.
PS2	Not met	No de novo observation (with confirmed maternity and paternity) has been reported for this variant.
PS3	Met	The BARD1 p.Gly623Glu variant was directly tested in a homology-directed DNA repair (HDR) reporter assay in HeLa cells. The variant showed significantly reduced HDR activity (14–19% of wild-type), classified as intermediate function. It was expressed and soluble but failed to bind BRCA1, disrupting a protein–protein interaction critical for DNA repair function. This functional evidence supports a deleterious effect on protein function.	PMID:26350354
PS4	Not met	No case-control study demonstrating statistically significant enrichment of this variant in affected individuals versus controls was identified.
PS5	Not met	No evidence that this specific nucleotide change (c.1868G>A) has been previously established as a pathogenic variant in any context.
PM1	Not met	Gly623 is located in the C-terminal region of BARD1, which contributes to BRCA1 binding and HDR function. The G623E mutant disrupts BRCA1 binding. However, the exact domain boundaries for a well-characterized critical functional domain encompassing residue 623 are not clearly defined in the available evidence. The variant is not in a statistically significant cancer hotspot (cancerhotspots.org). While the C-terminal region is functionally important, domain-level evidence is insufficient to apply PM1 at this position.	PMID:26350354
PM2	Met	This variant is present at very low frequency in population databases: gnomAD v2.1 AF = 0.00119% (3/251,210 alleles), gnomAD v4.1 AF = 0.00229% (37/1,613,832 alleles), grpmax FAF = 2.233e-05. All observed frequencies are well below the 0.1% threshold for PM2 in the generic ACMG framework. No homozygotes have been observed.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue comparator variants with expert-panel pathogenic classification could be identified for automated PM5 candidate harvesting.	pm5_candidates
PM6	Not met	No de novo observation (with confirmed maternity and paternity) has been reported for this variant.
PP1	Not met	No segregation data (co-segregation with disease in multiple affected family members) is available for this variant.
PP2	Not met	PP2 requires that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease. For BARD1, this has not been well established — the gene's status as a definitive HBOC susceptibility gene remains under investigation, and the rate of pathogenic versus benign missense variation is not clearly defined.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.388 (intermediate, not meeting typical pathogenic thresholds). BayesDel score is 0.016 (strongly benign-leaning). SpliceAI predicts no significant splice impact (max delta = 0.05). The in silico evidence does not reach the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No variant-specific phenotype data demonstrating that the patient's phenotype or family history is highly specific for BARD1-related disease has been identified for this variant.
PP5	Not met	The ClinVar classification for this variant is Uncertain Significance with review status 'criteria provided, single submitter' (1-star). The global PP5 rule requires ClinVar 3-star expert panel classification to apply at supporting strength. This variant does not meet that threshold.	clinvar
BA1	Not met	The maximum population frequency of this variant (gnomAD v4.1 AF = 0.00229%) is far below the 1% threshold for BA1 in the generic ACMG framework.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population frequency of this variant (gnomAD v4.1 AF = 0.00229%) is below the 0.3% threshold for BS1 in the generic ACMG framework.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that this variant has been observed in a healthy adult individual for a fully penetrant disorder with clear dominant inheritance.
BS3	Not met	The well-established functional study (Lee et al., 2015, PMID:26350354) directly tested p.Gly623Glu and demonstrated significantly reduced HDR function (14–19% of wild-type). The variant was classified as intermediate — not normal/functional. This functional evidence does NOT support a benign effect; rather it supports a deleterious effect.	PMID:26350354
BS4	Not met	No segregation data (lack of co-segregation with disease in affected family members) is available for this variant.
BP1	Not met	BP1 requires that the gene has a primary truncating mechanism and that missense variants are not a known cause of disease. BARD1 has known pathogenic missense variants (e.g., in the RING domain) that disrupt BRCA1 binding and HDR function. Therefore BP1 does not apply.	PMID:26350354
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 suggest no impact on the gene product. BayesDel score is 0.016 (strongly benign-leaning). SpliceAI predicts no splicing impact (max delta = 0.05). REVEL score of 0.388 is indeterminate. The preponderance of in silico evidence suggests a benign effect.	revel bayesdel spliceai
BP5	N/A	No alternate molecular basis for disease has been identified in the case materials that would make this variant less likely to be causative.
BP6	Not met	The ClinVar classification for this variant is Uncertain Significance with review status 'criteria provided, single submitter' (1-star). The global BP6 rule requires ClinVar 3-star expert panel benign/likely benign classification to apply at supporting strength. This variant does not meet that threshold.	clinvar
BP7	N/A	BP7 applies to synonymous variants where splicing prediction algorithms predict no impact. NM_000465.4:c.1868G>A is a missense variant (p.Gly623Glu), not a synonymous variant.

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