Starting
Initialising…
0%
BARD1
Final classification
Benign
BARD1 c.722C>G · p.Ser241Cys
BARD1

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.

Gene
BARD1
Transcript
NM_000465.4
HGVS · transcript:coding
NM_000465.4:c.722C>G
Consequence
N/A
GRCh38
chr2:214781152 G>C
GRCh37
chr2:215645876 G>C
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting; combination = 1 stand-alone benign + 1 strong benign + 2 supporting benign, which maps to Benign.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting; combination = 1 stand-alone benign + 1 strong benign + 2 supporting benign, which maps to Benign.
Classification rationale
BA1BS1BP4BP6 Benign
BARD1 c.722C>G

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.1 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.2 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.3 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.4 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.5 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.6

BA1 + BS1 + BP4 + BP6 Benign
3 revelbayesdelspliceai ↗
6 generic_acmg_combination_rules
Gene diagram · NM_000465.4 · variants mapped to exon structure
BARD1 NM_000465.4
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength very strong supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
Rationale
Select a criterion.
Sources
Evidence used
    Gaps remaining
      Rule
      Research & evidence
      Population frequency · supports benign
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 0.000603202; MAF= 0.06032%, 951/1576586 alleles, homozygotes = 19) and has highest observed frequency in the East Asian population (AF= 0.0211151; MAF= 2.11151%, 943/44660 alleles, homozygotes = 19); grpmax FAF= 0.0199964.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 0.000134099; MAF= 0.01341%, 29/216258 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00168229; MAF= 0.16823%, 28/16644 alleles, homozygotes = 0); grpmax FAF= 0.00119534.
      🇨🇦 CA
      This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.06% · 951 / 1,576,586
      19 hom · FAF 2%
      East Asian
      943 / 44,660
      2.1%
      19 hom
      Remaining individuals
      8 / 60,750
      0.013%
      + 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
      gnomAD v2.1
      0.013% · 29 / 216,258
      0 hom · FAF 0.12%
      East Asian
      28 / 16,644
      0.17%
      Remaining individuals
      1 / 5,054
      0.02%
      + 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), South Asian)
      gnomAD Canada 🇨🇦
      0.016% · 3 / 18,420
      0 hom · FAF 0.027%
      East Asian
      2 / 1,338
      0.15%
      Remaining individuals
      1 / 1,138
      0.088%
      + 7 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, European (Finnish), Middle Eastern, European (non-Finnish), South Asian)
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (6 clinical laboratories). (ClinVarID = 136497)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.19). REVEL score = 0.312. BayesDel score = -0.180224.
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BARD1, a tumor suppressor involved in the DNA damage response, is altered by mutation in breast and ovarian cancers.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Not in COSMIC / hotspots
      COSMIC
      This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 9 PMIDs not cited in assessment
      23056176 ↗ Identification of functional SNPs in BARD1 gene and in silico analysis of damaging SNPs: based on data procured from dbSNP database. CLINVAR
      25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR
      26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
      26692440 ↗ Clinicopathologic Features and Germline Sequence Variants in Young Patients (≤40 Years Old) With Pancreatic Ductal Adenocarcinoma. CLINVAR
      14550946 ↗ Mutational analysis of BARD1 in familial breast cancer patients in Japan. CLINVAR
      24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR
      24432435 ↗ PMID 24432435 CLINVAR
      26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR