NM_000465.4:c.1217G>A (p.Arg406Gln) is a missense variant in BARD1 exon 4. This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.006% (17/282,356 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 0.002% (39/1,613,954 alleles, 1 homozygote), meeting PM2 (supporting).1 Multiple lines of computational evidence predict a benign effect: REVEL score 0.117, BayesDel score -0.406678, and SpliceAI max delta 0.05, meeting BP4 (supporting).2 Functional studies show conflicting results: p.R406Q is fully functional in homology-directed repair (149% of wild-type activity; PMID:26350354) but shows partially impaired apoptosis in patient-derived lymphoblastoid cells (TUNEL and Annexin V assays; PMID:31371347). Neither PS3 nor BS3 is met due to inconsistent evidence across assay types.3 This variant has been reported in two unrelated patients with early-onset colorectal cancer (ages 24 and 37; PMID:31371347), but colorectal cancer is not the classic BARD1-associated phenotype (hereditary breast and ovarian cancer).4 In ClinVar (Variation ID 127713), this variant is classified as Uncertain Significance by 8 clinical laboratories and Likely Benign by 1 laboratory, with no expert panel review available.5 No de novo, segregation, or case-control data are available. No pathogenic missense variant at the same residue has been identified (PM5 not met).
BARD1
Final classification
VUS
PM2BP4
BARD1
c.1217G>A
p.Arg406Gln
This variant
NM_000465.4:c.1217G>A (p.Arg406Gln) is a missense variant in BARD1 exon 4.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BARD1 c.1217G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
Gene diagram
· NM_000465.4 · variants mapped to exon structure
BARD1
NM_000465.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 22 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.006% (17/282,356 alleles, 0 homozygotes) and gnomAD v4.1 allele frequency 0.002% (39/1,613,954 alleles, 1 homozygote). The frequency is well below the 0.1% threshold for PM2 under generic ACMG rules. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: AF=6.02e-05 (17/282356 alleles0 homozygotes)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on gene product. REVEL score is 0.117 (benign-predicting, below 0.5 threshold). BayesDel score is -0.406678 (benign-predicting, negative value). SpliceAI max delta score is 0.05 (no predicted splicing impact, well below 0.2 threshold). All three in silico tools consistently predict a benign effect.
REVEL: 0.117 (benign-predicting)BayesDel: -0.406678 (benign-predicting)SpliceAI max delta: 0.05 (no splicing impact)
Assessed · not applied
· 12 not met · 10 not assessed
Pathogenic
PVS1
This is a missense variant (c.1217G>A, p.Arg406Gln) and does not fall into a null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus).
PS1
No evidence of a different nucleotide change at this position producing the same amino acid change (p.Arg406Gln) that has been established as pathogenic.
PS2
No de novo testing was performed for the two patients (L75, S490) reported in PMID:31371347.
PS3
Well-established functional studies do not demonstrate a consistent damaging effect.
PS4
No case-control study comparing variant prevalence in affected individuals versus controls is available.
PM1
Residue 406 is not located in a statistically significant mutational hotspot, and the variant is observed in population databases (gnomAD v2.1 AF=0.006%, v4.1 AF=0.002%), indicating it is not in a critical invariant functional domain.
PM5
No pathogenic missense variant at the same amino acid residue (Arg406) was identified in ClinVar or the literature.
PM6
No de novo data are available for this variant.
PP1
No co-segregation data are available.
PP2
No missense constraint Z-score or HCI prior score is available for BARD1 to assess whether the gene has a low rate of benign missense variation.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
The patient phenotype is not highly specific for BARD1-related disease.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The variant allele frequency is far below the 1% BA1 threshold.
BS1
The variant allele frequency is below the 0.3% BS1 threshold for non-VCEP genes.
BS2
No data are available regarding observation of this variant in healthy adults with complete ascertainment and full penetrance evaluation.
BS3
Well-established functional studies do not consistently show no damaging effect.
BS4
No segregation data are available.
BP1
BARD1 is not a gene in which only truncating variants cause disease.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant.
BP5
No data are available regarding an alternate molecular basis for disease in patients carrying this variant.
BP6
No reputable source has classified this variant as benign.
N/A · 4
PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.41643e-05; MAF= 0.00242%, 39/1613954 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000263499; MAF= 0.02635%, 24/91082 alleles, homozygotes = 0); grpmax FAF= 0.00018075.
v2.1
This variant is present in gnomAD v2.1 (AF= 6.02077e-05; MAF= 0.00602%, 17/282356 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000451128; MAF= 0.04511%, 9/19950 alleles, homozygotes = 0); grpmax FAF= 0.00021575.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0024%
· 39 / 1,613,954
1 hom · FAF 0.018%
1 hom · FAF 0.018%
South Asian 24 / 91,082 |
0.026% |
East Asian 7 / 44,890 |
0.016% |
Remaining individuals 4 / 62,478 |
0.0064% 1 hom |
African/African American 1 / 74,918 |
0.0013% |
European (non-Finnish) 3 / 1,179,980 |
0.00025% |
+ 5 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.006%
· 17 / 282,356
0 hom · FAF 0.022%
0 hom · FAF 0.022%
East Asian 9 / 19,950 |
0.045% |
South Asian 8 / 30,606 |
0.026% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
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) and as Likely benign (1 clinical laboratory). (ClinVarID = 127713)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.117. BayesDel score = -0.406678.
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 previously been reported in somatic cancers (COSMIC; COSV53611525, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
23012255 ↗
ESMO Consensus Guidelines for management of patients with colon and rectal cancer. a personalized approach to clinical decision making.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26350354 ↗
Functional Analysis of BARD1 Missense Variants in Homology-Directed Repair of DNA Double Strand Breaks.
CLINVAR
25373533 ↗
Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.
CLINVAR
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
19042984 ↗
National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers.
CLINVAR