LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-22
Case ID: NM_000465.4_c.722C_G_20260622_153629
Framework: ACMG/AMP 2015
Variant classification summary

NM_000465.4:c.722C>G

BARD1  · NP_000456.2:p.(Ser241Cys)  · NM_000465.4
GRCh37: chr2:215645876 G>C  ·  GRCh38: chr2:214781152 G>C
Gene: BARD1 Transcript: NM_000465.4
Final call
Benign
BA1 stand-alone benign BS1 strong BP4 supporting BP6 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BARD1
Transcript
NM_000465.4
Protein
NP_000456.2:p.(Ser241Cys)
gnomAD AF
0.0006032021088605379 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
This variant is present in gnomAD v4.1 at an East Asian allele frequency of 2.11% (943/44,660 alleles) with 19 homozygotes and a grpmax filtering allele frequency of 2.0%, exceeding the 1% BA1 stand-alone benign threshold and establishing it as a common polymorphism incompatible with a highly penetrant Mendelian disorder.
2
The variant is classified as Benign in ClinVar (Variation ID 136497) with consensus from 9 clinical testing laboratories reporting Benign and 6 reporting Likely benign.
3
Multiple in silico predictors are consistent with a benign effect: REVEL score 0.312, BayesDel score -0.180, and SpliceAI maximum delta score 0.19 indicate no significant impact on protein function or splicing.
4
The variant was listed among 11 BARD1 nsSNPs predicted as 'not tolerated' by SIFT (TI=0.04) in an in silico screening study (PMID:23056176), but was not classified as damaging by PolyPhen and was not among the four SNPs identified as deleterious by both methods. This in silico analysis does not alter the benign classification.
5
No variant-specific functional studies, de novo reports, or segregation data were identified. The variant has not been reported as pathogenic by any reputable source.
6
Final classification: Benign. BA1 (stand-alone benign) is met. BS1 (strong benign) and BP4, BP6 (supporting benign) provide additional support. No pathogenic criteria are met.
Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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 This is a missense substitution (c.722C>G, p.Ser241Cys) in exon 4 and does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Generic PVS1 framework does not apply.
pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1 Not met No previously established pathogenic variant resulting in the same amino acid change (p.Ser241Cys) via a different nucleotide change was identified. The exact variant is classified as Benign in ClinVar.
clinvar pm5_candidates
PS2 Not met No de novo occurrence of this variant was reported in any reviewed source. PS2 requires confirmation of de novo status with both maternity and paternity confirmed.
PS3 Not met No well-established in vitro or in vivo functional studies were identified for this variant. The only relevant publication (PMID:23056176) is a purely in silico bioinformatics analysis using SIFT and PolyPhen; it does not include experimental functional assays. OncoKB found no variant-specific reviewed functional evidence.
PMID:23056176 oncokb
PS4 Not met The variant is observed at high frequency in population databases (gnomAD v4.1 East Asian AF 2.11%, 19 homozygotes), indicating it is a common polymorphism. No statistically significant enrichment in cases versus controls can be demonstrated. Observed in breast cancer cohorts (PMID:14550946 Japanese breast cancer study) but population frequency precludes case-control significance.
gnomad_v4 gnomad_v2
PS5 Not met No reputable source reports this variant as pathogenic. ClinVar classifies this variant as Benign (9 clinical laboratories) and Likely benign (6 clinical laboratories).
clinvar
PM1 Not met The variant does not lie in a statistically significant mutational hotspot. While BARD1 has well-established functional domains (RING, ankyrin repeats, BRCT), residue 241 is not in a critical domain with absence of benign variation. The variant has substantial benign population variation (2.1% EAS AF, 19 homozygotes).
gnomad_v4
PM2 Not met gnomAD grpmax filtering allele frequency of 0.12% (v2.1) and 2.0% (v4.1) exceeds the 0.1% threshold for PM2. The variant is present at appreciable frequency in population databases, particularly in East Asian populations.
gnomad_v2 gnomad_v4
PM5 N/A PM5 requires a pathogenic missense variant at the same amino acid residue. No same-residue pathogenic comparator variants were identified in ClinVar; PM5 candidate harvesting was inconclusive.
pm5_candidates
PM6 Not met No de novo report was identified for this variant. PM6 requires a de novo observation with maternity and paternity confirmation.
PP1 Not met No segregation data were identified for this variant. PP1 requires cosegregation with disease in multiple affected family members.
PP2 Not met PP2 applies to genes with a low rate of benign missense variation where missense variants are a common disease mechanism. BARD1 has both truncating and missense pathogenic variants, but benign missense variation is also common. The high population frequency of this variant (2.1% EAS) indicates benign missense variation occurs in BARD1.
gnomad_v4
PP3 Not met Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.312 (below typical 0.5 pathogenic threshold), BayesDel score is -0.180 (benign range), and SpliceAI max delta is 0.19 (no predicted splicing impact). Although SIFT in PMID:23056176 predicted this variant as 'not tolerated' (TI=0.04), this is not corroborated by other computational tools and PolyPhen did not classify it as damaging.
revel bayesdel spliceai PMID:23056176
PP4 Not met No specific patient phenotype or family history consistent with BARD1-related hereditary breast and ovarian cancer syndrome was provided for assessment. PP4 requires a phenotype highly specific for a single genetic etiology.
PP5 Not met No reputable source reports this variant as pathogenic. ClinVar aggregate classification is Benign (ID 136497). No expert panel has classified this variant as pathogenic.
clinvar
BA1 Met gnomAD v4.1 reports an East Asian allele frequency of 2.11% (943/44,660 alleles) with 19 homozygotes, and a grpmax filtering allele frequency of 2.0%. These exceed the 1% BA1 threshold, establishing this variant as a common polymorphism incompatible with a highly penetrant Mendelian disease.
gnomad_v4
BS1 Met gnomAD v4.1 grpmax filtering allele frequency of 2.0% and East Asian allele frequency of 2.11% far exceed the 0.3% BS1 threshold. gnomAD v2.1 grpmax FAF of 0.12% is below 0.3% but superseded by the larger v4.1 dataset.
gnomad_v4 gnomad_v2
BS2 Not met BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. While 19 homozygotes are present in gnomAD v4.1, gnomAD is a population database without individual phenotype data. BARD1-associated cancer predisposition has adult onset and variable penetrance; gnomAD homozygote counts alone cannot confirm healthy adult status with expected early-onset penetrance.
gnomad_v4
BS3 Not met No well-established in vitro or in vivo functional studies demonstrating a neutral effect were identified. In silico predictions (REVEL, BayesDel, SpliceAI) suggest a benign effect, but BS3 requires experimental functional evidence, not computational predictions alone.
revel bayesdel spliceai
BS4 Not met No segregation data were available to assess lack of cosegregation with disease in affected family members.
BP1 Not met BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. While BARD1 loss-of-function variants are established in hereditary breast and ovarian cancer, pathogenic missense variants in BARD1 have also been reported; the gene does not meet the strict BP1 criterion of 'primarily truncating variants cause disease.'
BP2 Not met No evidence was found of this variant occurring in trans with a known pathogenic BARD1 variant in a fully penetrant dominant disorder.
BP4 Met Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.312 (below pathogenic threshold), BayesDel score is -0.180 (benign range), and SpliceAI max delta score is 0.19 (no predicted splicing impact). Convergent benign predictions from independent in silico tools meet BP4 at supporting level.
revel bayesdel spliceai
BP5 Not met No alternate molecular basis for disease was identified in a case harboring this variant. BP5 requires observation of the variant in a case with a confirmed alternative cause of disease.
BP6 Met ClinVar reports this variant as Benign by consensus of 9 clinical laboratories and Likely benign by 6 additional laboratories (ClinVar Variation ID 136497). The aggregate classification from multiple clinical testing laboratories is Benign, meeting BP6 at supporting level.
clinvar
BP7 N/A BP7 applies to synonymous variants with no predicted splice impact. This is a missense substitution (c.722C>G, p.Ser241Cys) and does not qualify.
BP3 N/A In-frame deletions/insertions in a repetitive region without a known function. Variant is a missense substitution.
PM3 N/A Detected in trans with a pathogenic variant for a recessive disorder. BARD1-associated disease has autosomal dominant inheritance.
PM4 N/A Protein length changes due to in-frame deletions/insertions or stop-loss. Variant is a missense substitution.
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