NM_000465.4:c.1217G>A

BARD1 · NP_000456.2:p.(Arg406Gln) · NM_000465.4

GRCh37: chr2:215645381 C>T · GRCh38: chr2:214780657 C>T

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.(Arg406Gln)

gnomAD AF

2.4164257469543743e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

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).

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.

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).

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.

No de novo, segregation, or case-control data are available. No pathogenic missense variant at the same residue has been identified (PM5 not met).

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	Not met	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). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No evidence of a different nucleotide change at this position producing the same amino acid change (p.Arg406Gln) that has been established as pathogenic. No alternate nucleotide variants at codon 406 were identified.
PS2	Not assessed	No de novo testing was performed for the two patients (L75, S490) reported in PMID:31371347. Parental samples were not analyzed.	PMID:31371347
PS3	Not met	Well-established functional studies do not demonstrate a consistent damaging effect. PMID:26350354 showed p.R406Q is fully functional in homology-directed repair (HDR) assay (149% of wild-type activity). PMID:31371347 reported partially impaired apoptosis in patient-derived lymphoblastoid cells (TUNEL and Annexin V assays, 0.4-0.8 fold of controls) but normal BARD1-BRCA1 colocalization and RAD51 foci formation. The functional evidence is conflicting across assays and does not meet the threshold for well-established damaging effect.	PMID:26350354 PMID:31371347
PS4	Not assessed	No case-control study comparing variant prevalence in affected individuals versus controls is available. Two cases with colon cancer reported in PMID:31371347, but this is insufficient for statistical comparison.	PMID:31371347
PS5	N/A	PS5 is not a criterion in the ACMG/AMP 2015 guidelines (PMID:25741868). The generic ACMG framework used for this case does not include PS5.
PM1	Not met	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.	gnomad_v2 gnomad_v4
PM2	Met	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 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per instruction — not in the assess list for this case.
PM4	N/A	Skipped per instruction — not applicable for substitution variants.
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Arg406) was identified in ClinVar or the literature. The automated PM5 candidate search found no eligible comparator variants at this residue.	clinvar
PM6	Not assessed	No de novo data are available for this variant. The two patients reported in PMID:31371347 did not undergo parental testing.	PMID:31371347
PP1	Not assessed	No co-segregation data are available. The two patients in PMID:31371347 (L75 and S490) are unrelated, and no family testing for this variant was performed.	PMID:31371347
PP2	Not assessed	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. HCI prior lookup returned 'gene_not_supported' for BARD1.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.117 (below the 0.5 threshold, predicting benign). BayesDel score is -0.406678 (negative, predicting benign). SpliceAI max delta score is 0.05 (no predicted splicing impact). All in silico tools predict a benign effect.	revel bayesdel spliceai
PP4	Not met	The patient phenotype is not highly specific for BARD1-related disease. The two reported cases in PMID:31371347 presented with early-onset colorectal cancer (ages 24 and 37), which is not the classic BARD1-associated phenotype (hereditary breast and ovarian cancer). No patients with breast or ovarian cancer carrying this variant were identified.	PMID:31371347
PP5	Not met	No reputable source has classified this variant as pathogenic. In ClinVar (Variation ID 127713), 8 clinical laboratories classify it as Uncertain Significance and 1 laboratory classifies it as Likely Benign. No expert panel review is available. PMID:31371347 suggests the variant 'may be pathogenic' but explicitly states there is insufficient evidence for reclassification per ACMG criteria.	clinvar PMID:31371347
BA1	Not met	The variant allele frequency is far below the 1% BA1 threshold. gnomAD v2.1 AF=0.006%, gnomAD v4.1 AF=0.002%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency is below the 0.3% BS1 threshold for non-VCEP genes. gnomAD v2.1 AF=0.006%, gnomAD v4.1 AF=0.002%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults with complete ascertainment and full penetrance evaluation.
BS3	Not met	Well-established functional studies do not consistently show no damaging effect. While PMID:26350354 demonstrated that p.R406Q is fully functional in HDR (149% of wild-type activity), PMID:31371347 reported partially impaired apoptosis in patient-derived lymphoblastoid cells. The conflicting functional evidence across different assays precludes application of BS3.	PMID:26350354 PMID:31371347
BS4	Not assessed	No segregation data are available. Family members of the two reported patients in PMID:31371347 were not tested for this variant.
BP1	Not met	BARD1 is not a gene in which only truncating variants cause disease. Both missense and truncating pathogenic variants have been reported in BARD1, and functional studies of missense variants (e.g., PMID:26350354, PMID:31371347) demonstrate that missense changes can affect protein function.	PMID:26350354 PMID:31371347
BP2	Not assessed	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.
BP3	N/A	Skipped per instruction — trivially not applicable (BP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant).
BP4	Met	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 bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in patients carrying this variant.
BP6	Not met	No reputable source has classified this variant as benign. In ClinVar, 8 clinical laboratories classify it as Uncertain Significance and only 1 laboratory (Ambry Genetics, SCV000275338) classifies it as Likely Benign. A single Likely Benign classification with 8 conflicting VUS classifications does not constitute a reputable source consensus for benign classification.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant (c.1217G>A, p.Arg406Gln) is a missense variant, not synonymous.

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