NM_000465.4:c.928T>G

BARD1 · NP_000456.2:p.(Ser310Ala) · NM_000465.4

GRCh37: chr2:215645670 A>C · GRCh38: chr2:214780946 A>C

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.(Ser310Ala)

gnomAD AF

6.197100005081622e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This variant is a missense substitution in BARD1 (NM_000465.4:c.928T>G, p.Ser310Ala) located in exon 4. BARD1 is a tumor suppressor gene involved in the DNA damage response, with germline loss-of-function variants associated with hereditary breast and ovarian cancer susceptibility.

This variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (AF = 6.20e-6; 10/1,613,658 alleles, all in the European non-Finnish subpopulation; 0 homozygotes). This extremely low population frequency meets PM2 at supporting strength (well below the 0.1% threshold).

Multiple lines of computational evidence predict a benign effect. REVEL score is 0.086 (strongly benign-leaning). BayesDel score is -0.575 (benign-leaning). SpliceAI max delta score is 0.02, predicting no splicing impact. Multiple independent clinical laboratories concurred that in silico tools predict a benign effect, with Labcorp noting five of five tools predicted no impact. This meets BP4 at supporting strength.

No variant-specific functional studies, case-control data, segregation data, or de novo reports were identified. The variant has been reported in ClinVar predominantly as a Variant of Uncertain Significance (5 clinical laboratories) with one Likely benign classification (Ambry Genetics). No expert panel review has been performed.

Applying generic ACMG/AMP 2015 combination rules (PMIDs:25741868): PM2 (supporting) + BP4 (supporting) results in a final classification of Variant of Uncertain Significance, as the evidence supporting pathogenicity and benign impact are insufficient to reach a more definitive 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	This is a missense variant (p.Ser310Ala) in BARD1 exon 4. It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework is not applicable to missense variants.	pvs1_generic_framework
PS1	Not assessed	No data available on whether the same amino acid change (p.Ser310Ala) has been previously reported as pathogenic. No comparator variants at this residue with established pathogenicity were identified in the PM5 candidate search.
PS2	Not assessed	No de novo data available for this variant. No publication reporting a confirmed de novo occurrence of NM_000465.4:c.928T>G was identified.
PS3	Not met	No variant-specific functional studies have been reported for NM_000465.4:c.928T>G. ClinVar submitter Color Diagnostics noted: 'to our knowledge, functional studies have not been reported for this variant.' REVEL score (0.086) and BayesDel score (-0.575) are both benign-leaning but represent in silico predictions, not functional evidence.	clinvar revel bayesdel
PS4	Not assessed	No variant-specific case-control or prevalence data available. Tung et al. (PMID:26976419) and BCAC (PMID:33471991) studied BARD1 in breast cancer cohorts but did not report this specific variant. Insufficient data to assess enrichment in affected individuals.
PS5	Not assessed	No de novo data available. PS5 requires a confirmed de novo occurrence with confirmed maternity and paternity; no such data exists for this variant.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot in BARD1. The hotspot analysis found no enrichment at this residue.
PM2	Met	This variant is absent from gnomAD v2.1 (exome) and has an extremely low allele frequency in gnomAD v4.1 (AF = 6.20e-6, 10/1,613,658 alleles, 0 homozygotes; grpmax FAF = 4.29e-06). The observed frequency of 0.00062% is well below the 0.1% threshold for PM2 in non-VCEP contexts. Absent from all subpopulations except European (non-Finnish) where it is present at 8.48e-6. Not available in gnomAD-Canada.	gnomad_v2 gnomad_v4
PM5	N/A	No comparator variants at the same amino acid residue (Ser310) with established pathogenicity were identified. The automated PM5 candidate search found zero candidates.
PM6	Not assessed	No de novo data available. PM6 requires a confirmed de novo occurrence without confirmed maternity and paternity; no such data exists for this variant.
PP1	Not assessed	No segregation data available for this variant in affected families.
PP2	Not assessed	PP2 applies to genes where missense variants are a common mechanism of disease with a low rate of benign missense variation. For BARD1, loss-of-function is the primary disease mechanism, and systematic missense constraint data were not available for this assessment. Cannot apply PP2 without gene-specific missense constraint metrics.
PP3	Not met	Multiple in silico tools predict a benign effect for this variant. REVEL score is 0.086 (strongly benign-leaning, well below the typical 0.5 pathogenic threshold). BayesDel score is -0.575 (benign-leaning). SpliceAI max delta score is 0.02 (no predicted splicing impact). Multiple ClinVar submitters concurred that in silico analysis predicts benign effect.	revel bayesdel spliceai clinvar
PP4	Not assessed	No specific patient phenotype information available for this variant. PP4 requires that the variant is observed in a patient with a phenotype highly specific for the gene/disease; no such data were identified.
PP5	Not met	This variant is classified as Uncertain Significance by 5 clinical laboratories in ClinVar and as Likely benign by 1 laboratory (Ambry Genetics). There is no expert panel classification. The ClinVar review status is 'criteria provided, single submitter' and there is no recent consensus pathogenic classification from a reputable source.	clinvar
BA1	Not met	The allele frequency in gnomAD v4.1 is 6.20e-6 (0.00062%), well below the 1% BA1 threshold. Not applicable.	gnomad_v4
BS1	Not met	The allele frequency in gnomAD v4.1 is 6.20e-6 (0.00062%), well below the 0.3% BS1 threshold. Not applicable.	gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult individuals with full penetrance expected at an early age. The gnomAD observations could be from healthy controls but no specific phenotype data for carriers are available.
BS3	Not met	No functional studies demonstrating no deleterious effect have been reported for this variant. REVEL (0.086) and BayesDel (-0.575) scores are benign-leaning in silico predictions, which are addressed under BP4, not BS3.	clinvar
BS4	Not assessed	No segregation data available to assess lack of cosegregation with disease.
BP1	Not assessed	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. For BARD1, both truncating and missense variants have been associated with disease, and sufficient systematic data to determine that only truncating variants are pathogenic are not available.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant in BARD1 or another gene for a fully penetrant dominant disorder.
BP4	Met	Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.086 (strongly benign-leaning). BayesDel score is -0.575 (benign-leaning). SpliceAI max delta score is 0.02 (no predicted splicing impact). Multiple independent ClinVar submitters (GeneDx, Labcorp/Women's Health and Genetics) concurred that in silico analysis predicts a benign effect, with Labcorp noting 'five of five in-silico tools predict a benign effect of the variant on protein function.'	revel bayesdel spliceai clinvar
BP5	Not assessed	No data on an alternative molecular basis for disease in a case with this variant. BP5 requires observation in a case with an alternative molecular basis for disease; no such data available.
BP6	Not met	No expert panel or reputable source has classified this variant as benign. ClinVar classification is predominantly Uncertain Significance (5 laboratories), with one Likely benign submission (Ambry Genetics). No expert panel classification exists.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or a new splice site, and the nucleotide is not highly conserved. This variant is a missense substitution (c.928T>G, p.Ser310Ala), not a synonymous variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without a known function. This variant is a missense substitution.
PM3	N/A	PM3 requires observation in trans with a pathogenic variant for recessive disorders. BARD1 is not established as a recessive disease gene.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This variant is a missense substitution.

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