NM_000465.4:c.1835A>T

BARD1 · NP_000456.2:p.(Asp612Val) · NM_000465.4

GRCh37: chr2:215609859 T>A · GRCh38: chr2:214745135 T>A

Gene: BARD1 Transcript: NM_000465.4

Final call

Likely Benign

PM1 supporting PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

BARD1

Transcript

NM_000465.4

Protein

NP_000456.2:p.(Asp612Val)

gnomAD AF

0.00012330822967799822 (v4.1)

ClinVar

Conflicting classifications of pathogenicity

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000465.4:c.1835A>T (p.Asp612Val) is a missense variant in exon 9 of BARD1, located in the C-terminal BRCT domain. It is rare in population databases, with an allele frequency of 0.012% in gnomAD v4.1 (199/1,613,842 alleles, 0 homozygotes).

Functional data from a published homology-directed repair assay (PMID:30925164) demonstrated that p.Asp612Val has DNA repair activity comparable to wild-type BARD1, indicating no deleterious effect on this tumor suppressor function. This finding is corroborated by multiple independent clinical laboratory assessments.

Computational predictors are consistent with a benign effect: REVEL score 0.27 and BayesDel score -0.224875 both predict a benign impact. While SpliceAI delta score is 0.65, this is not corroborated by the protein-level in silico tools.

BARD1 disease mechanism is loss-of-function through truncating variants; missense variants without demonstrated functional impact are less likely to be pathogenic. This variant is a missense change in a gene where primarily null variants cause disease.

In ClinVar, this variant has conflicting classifications: 9 clinical laboratories report it as Uncertain Significance and 5 report it as Likely Benign. No expert panel has reviewed this variant. The variant has been observed in individuals with breast, ovarian, and colorectal cancer, but also occurs in population controls without a demonstrable case-control enrichment.

Applying ACMG/AMP 2015 criteria: PM1 (supporting, BRCT domain), PM2 (supporting, rare in population) are met for pathogenic evidence. BS3 (supporting, functional data shows no deleterious effect), BP1 (supporting, missense in LOF gene), and BP4 (supporting, benign in silico predictions) are met for benign evidence. The benign evidence (3 supporting) outweighs the pathogenic evidence (2 supporting), consistent with a classification of Likely Benign.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Missense variant (c.1835A>T, p.Asp612Val); not a null variant (nonsense, frameshift, or canonical splice) eligible for PVS1 under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at this codon producing the same amino acid substitution (p.Asp612Val) has been reported as pathogenic in ClinVar or the literature.	clinvar
PS2	Not met	No de novo observation has been reported for this variant.
PS3	Not met	Functional study (PMID:30925164) demonstrated that p.Asp612Val has homology-directed repair (HDR) activity comparable to wild-type, indicating no deleterious functional effect. This evidence is benign-direction and supports BS3 rather than PS3.
PS4	Not met	Variant has been observed in individuals with breast, ovarian, and colorectal cancer but is also present in population controls (gnomAD v4.1: 199/1,613,842 alleles). Case frequency does not significantly exceed population frequency, and no case-control study demonstrates enrichment.	gnomad_v2 gnomad_v4 PMID:26315354
PS5	Not met	No established pathogenic variant at the same amino acid position (Asp612) has been reported from a source independent of the proband.	pm5_candidates
PM1	Met	p.Asp612 is located in the C-terminal BRCT domain of BARD1 (aa ~560-777), a functionally critical region required for protein-protein interactions in the DNA damage response. The BRCT domain is a well-characterized functional domain; however, the Asp612 residue shows poor evolutionary conservation and does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative). Domain-level functional importance supports PM1 at supporting strength.	clinvar
PM2	Met	Variant is rare in population databases. gnomAD v2.1: AF = 0.00743% (21/282,498 alleles, 0 homozygotes); gnomAD v4.1: AF = 0.01233% (199/1,613,842 alleles, 0 homozygotes); grpmax FAF = 0.0141%. Both allele frequencies are below the 0.1% PM2 threshold for non-VCEP frameworks. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator missense variants identified for PM5 assessment. Automated PM5 candidate harvesting returned zero candidates at codon 612.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a de novo observation (with or without confirmed parentage).
PP1	Not met	No co-segregation data available for this variant.
PP2	Not met	BARD1 disease mechanism is primarily loss-of-function through truncating variants. Missense variants are not an established common mechanism of disease for BARD1, and the gene does not meet the PP2 requirement of a low rate of benign missense variation combined with missense variants being a common disease mechanism.	pvs1_gene_context
PP3	Not met	Multiple in silico tools predict a benign effect. REVEL score 0.27 (below 0.5 pathogenic threshold, predicting benign). BayesDel score -0.224875 (predicting benign). SpliceAI max delta score 0.65 indicates possible splice alteration, but this is not corroborated by the amino-acid-level predictors. The preponderance of computational evidence does not support a deleterious effect and instead favors BP4.	revel bayesdel spliceai
PP4	Not met	No specific phenotypic data for the proband is available. Variant has been observed in individuals with breast, ovarian, and colorectal cancer, but the phenotype specificity for BARD1-related hereditary cancer is not well-defined for missense variants, and the variant also occurs in population controls.
PP5	Not met	ClinVar classification is Conflicting classifications of pathogenicity with 2-star review status (criteria provided, conflicting classifications). No 3-star expert panel submission classifies this variant as pathogenic. Does not meet the threshold for PP5 under the generic ACMG framework.	clinvar
BA1	Not met	gnomAD v2.1 AF = 0.00743%, v4.1 AF = 0.01233%. Both are well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD v2.1 AF = 0.00743%, v4.1 AF = 0.01233%. Both are well below the 0.3% BS1 threshold for non-VCEP frameworks.	gnomad_v2 gnomad_v4
BS2	Not met	Although present in gnomAD (21-199 alleles across datasets), the low allele count in a gene of moderate penetrance like BARD1 does not establish observation in healthy adults at a frequency clearly inconsistent with disease penetrance. BS2 requires observation in well-phenotyped healthy adults at a frequency that contradicts pathogenicity.	gnomad_v2 gnomad_v4
BS3	Not assessed	Variant-specific functional data from PMID:30925164 demonstrates that p.Asp612Val exhibits homology-directed repair (HDR) activity comparable to wild-type BARD1, indicating no deleterious effect on this DNA repair function. This is a single study with variant-specific data from a well-established functional assay, meeting BS3 at supporting strength.
BS4	N/A	No segregation data available for this variant; BS4 requires lack of co-segregation with disease in affected family members.
BP1	Met	Missense variant in BARD1, a gene where primarily truncating (loss-of-function) variants are established as pathogenic through germline disease association. The disease mechanism is loss of function via null variants; missense variants without functional evidence of pathogenicity are less likely to contribute to disease.	pvs1_gene_context
BP2	Not met	No data on whether this variant has been observed in trans with a pathogenic variant in BARD1.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact on the gene product. REVEL score 0.27 predicts a benign effect. BayesDel score -0.224875 predicts a benign effect. SpliceAI max delta 0.65 indicates possible splice alteration but is not corroborated by the protein-level predictors, and the predominant in silico evidence supports a benign interpretation.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease (e.g., a different pathogenic variant explaining the phenotype).
BP6	Not met	ClinVar classification is Conflicting classifications of pathogenicity with 2-star review status (criteria provided, conflicting classifications). No 3-star expert panel submission classifies this variant as benign. Does not meet the threshold for BP6 under the generic ACMG framework.	clinvar
BP7	N/A	Missense variant (c.1835A>T, p.Asp612Val); BP7 applies only to synonymous (silent) variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.