NM_000465.4:c.764A>G

BARD1 · NP_000456.2:p.(Asn255Ser) · NM_000465.4

GRCh37: chr2:215645834 T>C · GRCh38: chr2:214781110 T>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.(Asn255Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BARD1 c.764A>G (p.Asn255Ser) variant has been reported in ClinVar predominantly as uncertain significance, with 11 uncertain significance submissions and 1 likely benign submission.

This variant is present at low frequency in population databases, with a total allele frequency of 0.00316% in gnomAD v2.1 and 0.00228% in gnomAD v4.1; the highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which remains below the 0.1% rarity threshold.

Available computational evidence is consistent with no significant functional impact, with SpliceAI predicting no significant splice effect (maximum delta score 0.04), REVEL 0.241, and BayesDel -0.546443.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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 variant is a missense substitution, c.764A>G (p.Asn255Ser), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although loss of function is an established disease mechanism for BARD1, available evidence does not support applying PVS1 to this specific variant.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No confirmed pathogenic variant producing the same amino acid change, p.Asn255Ser, was identified in the available evidence. Available evidence does not support applying PS1.	clinvar
PS2	Not assessed	No de novo occurrence with confirmed maternity and paternity was identified for this variant. Available evidence does not support applying PS2.	clinvar
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this exact variant was identified in the available evidence. Available evidence does not support applying PS3.	oncokb PMID:23056176
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control enrichment, odds ratio, or exact affected-carrier count sufficient for PS4 was identified. Available evidence does not support applying PS4.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no established critical functional domain with this exact residue was identified in the available evidence. Available evidence does not support PM1.	hotspots
PM2	Met	This variant is present at low frequency in gnomAD and remains below the non-VCEP rarity threshold of 0.1%. The highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which is below the 0.1% threshold and supports population rarity.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is intended for recessive disorders with trans observations. No recessive application was identified for this BARD1 hereditary cancer interpretation.
PM4	N/A	This variant is a missense substitution and does not cause a protein length change. PM4 does not apply.
PM5	Not assessed	No different pathogenic missense change at the same codon was identified in the available evidence. Available evidence does not support applying PM5.	clinvar
PM6	Not assessed	No assumed or unconfirmed de novo occurrence was identified for this variant. Available evidence does not support applying PM6.	clinvar
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not support applying PP1.	clinvar
PP2	Not assessed	Available evidence does not establish that pathogenic missense variation is a sufficiently common disease mechanism in BARD1 to support PP2 for this variant.	pvs1_gene_context
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together do not support applying PP3.	spliceai revel bayesdel
PP4	Not assessed	No phenotype or family-history information specific enough to BARD1-related disease was identified to support PP4.
PP5	N/A	PP5 is not applied because external assertions without independently reviewable evidence are not used for current ACMG/AMP interpretation.	clinvar
BA1	Not met	Population frequency does not reach the benign stand-alone threshold. The highest observed population frequency is 0.04224% in gnomAD v4.1, which is below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is below the benign strong threshold. The highest observed population frequency is 0.04224% in gnomAD v4.1, which is below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in a number of well-phenotyped unaffected individuals sufficient for BS2. No homozygotes were observed in gnomAD.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal or near-normal effect for this exact variant was identified. Available evidence does not support applying BS3.	oncokb PMID:23056176
BS4	Not assessed	No lack-of-segregation data were identified for this variant. Available evidence does not support applying BS4.	clinvar
BP1	Not assessed	Although loss of function is supported as a disease mechanism in BARD1, the available evidence does not establish that pathogenic missense variation is sufficiently uncommon to apply BP1 to this missense variant.	pvs1_gene_context
BP2	Not assessed	No co-occurrence data in trans with a pathogenic variant, or in cis in a way that would support BP2, were identified for this variant.
BP3	N/A	This variant is not an in-frame deletion or insertion in a repetitive region. BP3 does not apply.
BP4	Met	Multiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together support BP4.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation for the observed disease in an affected individual was identified in the available evidence. Available evidence does not support applying BP5.
BP6	N/A	BP6 is not applied because external benign assertions without independently reviewable evidence are not used as standalone evidence in current ACMG/AMP interpretation.	clinvar
BP7	N/A	This variant is a missense substitution and not a synonymous or deep intronic change. BP7 does not apply.

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