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).1 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.2 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.3 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.4 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.5
BARD1
Final classification
VUS
BARD1 c.1868G>A · p.Gly623Glu
BARD1
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM2 supporting, BP4 supporting; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PS3PM2
BP4
VUS
BARD1 c.1868G>A
PS3 + PM2 + BP4
→
VUS
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rulesPMID:25741868 ↗
Gene diagram
· NM_000465.4 · variants mapped to exon structure
BARD1
NM_000465.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
Pathogenic
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.
Direct functional testing of p.Gly623Glu in HDR reporter assay (HeLa-DR cellssiRNA depletion/rescue).HDR activity: 19% initially
✓
PM2
supporting
Pathogenic
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 v2.1: 3/251210 alleles (AF = 0.00119%)0 homozygotes.
✓
BP4
supporting
Benign
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.
BayesDel: 0.0162 (strongly benign-leaning).SpliceAI max delta: 0.05 (no predicted splicing impact).REVEL: 0.388 (indeterminate
Assessed · not applied
Pathogenic
PS2
No de novo observation (with confirmed maternity and paternity) has been reported for this variant.
PS4
No case-control study demonstrating statistically significant enrichment of this variant in affected individuals versus controls was identified.
PM1
Gly623 is located in the C-terminal region of BARD1, which contributes to BRCA1 binding and HDR function.
PM6
No de novo observation (with confirmed maternity and paternity) has been reported for this variant.
PP1
No segregation data (co-segregation with disease in multiple affected family members) is available for this variant.
PP2
PP2 requires that the gene has a low rate of benign missense variation and that missense variants are a common mechanism of disease.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
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
The ClinVar classification for this variant is Uncertain Significance with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
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.
BS1
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.
BS2
No evidence that this variant has been observed in a healthy adult individual for a fully penetrant disorder with clear dominant inheritance.
BS3
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).
BS4
No segregation data (lack of co-segregation with disease in affected family members) is available for this variant.
BP1
BP1 requires that the gene has a primary truncating mechanism and that missense variants are not a known cause of disease.
BP2
No observation of this variant in trans with a known pathogenic BARD1 variant has been reported.
BP6
The ClinVar classification for this variant is Uncertain Significance with review status 'criteria provided, single submitter' (1-star).
N/A · 5
PVS1 · PS1 · PM5 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.29268e-05; MAF= 0.00229%, 37/1613832 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.05094e-05; MAF= 0.00305%, 36/1179966 alleles, homozygotes = 0); grpmax FAF= 2.233e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.19422e-05; MAF= 0.00119%, 3/251210 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.64275e-05; MAF= 0.00264%, 3/113518 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0023%
· 37 / 1,613,832
0 hom · FAF 0.0022%
0 hom · FAF 0.0022%
European (non-Finnish) 36 / 1,179,966 |
0.0031% |
South Asian 1 / 91,072 |
0.0011% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 251,210
0 hom · FAF 0.0007%
0 hom · FAF 0.0007%
European (non-Finnish) 3 / 113,518 |
0.0026% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories). (ClinVarID = 142123)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.388. BayesDel score = 0.0162055.
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks.
Searched
c.1868G>Ap.Gly623GluG623Ep.G623E
Found
Lee et al. (2015) tested 29 BARD1 missense variants for homology-directed DNA repair (HDR) function in a HeLa cell reporter assay. The p.Gly623Glu variant showed significantly reduced HDR activity (14–19% of wild-type), classified as intermediate function. The mutant protein was soluble and well-expressed but failed to bind BRCA1 by co-immunoprecipitation, indicating disruption of a C-terminal protein–protein interaction critical for DNA repair.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data confirmed reduced HDR function and loss of BRCA1 binding. Referenced in PS3 assessment at moderate strength.
The lack of binding of the p.G623E mutant confirms that the C-terminus of BARD1 contributes to BRCA1 binding.
Location Table 1 (variant listing); Results, paragraphs on HDR assay and expression analysis; Figure 1C; Figure 3 (corrected backbone); Figure 4 (BRCA1 co-IP); Discussion. · Context HDR reporter assay (GFP-based), HeLa-DR-13-9 cells; siRNA depletion of endogenous BARD1 followed by plasmid rescue; co-immunoprecipitation for BRCA1 binding; immunoblot for protein expression. · full text
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
27498913 ↗
Monogenic and polygenic determinants of sarcoma risk: an international genetic study.
CLINVAR