BARD1 c.562C>T (p.Pro188Ser) is a missense variant in exon 4 of the BARD1 gene, a moderate-penetrance hereditary breast cancer susceptibility gene where loss of function is the established disease mechanism.1 The variant is extremely rare in population databases, with an allele frequency of 0.00040% in gnomAD v2.1 (1/249,196 alleles) and 0.00012% in gnomAD v4.1 (2/1,611,936 alleles), meeting PM2 at moderate strength.2 Multiple computational predictors consistently suggest a benign effect: REVEL score 0.05 (benign-tending), BayesDel score -0.484 (strongly benign-tending), and SpliceAI max delta 0.01 (no predicted splice impact), meeting BP4 at supporting benign strength.3 Pro188 is located outside the known critical functional domains of BARD1 (RING finger: aa 46-90; ANK repeats: aa 427-555; BRCT domains: aa 615-777) and is not a statistically significant hotspot residue; PM1 is not met. The variant is classified as Uncertain significance in ClinVar (2 clinical laboratories) with one additional Likely benign submission (Ambry Genetics), all at 1-star review status. No expert panel classification exists; PP5 and BP6 are not met.4 Two breast cancer cohort studies cited in ClinVar (PMID:32866190 and PMID:33646313) were reviewed in full text. BARD1 was mentioned at the gene level in both, but the specific variant c.562C>T (p.Pro188Ser) was not reported in either study. No variant-specific functional, segregation, or case-control data were identified.5
BARD1
Final classification
VUS
BARD1 c.562C>T · p.Pro188Ser
BARD1
BARD1 c.562C>T (p.Pro188Ser) is a missense variant in exon 4 of the BARD1 gene, a moderate-penetrance hereditary breast cancer susceptibility gene where loss of function is the established disease mechanism.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BARD1 c.562C>T
PM2 + BP4
→
VUS
1
pvs1_gene_context
3
revelbayesdelspliceai ↗
Gene diagram
· NM_000465.4 · variants mapped to exon structure
BARD1
NM_000465.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is extremely rare in population databases, with an overall allele frequency of 0.00040% (1/249,196 alleles) in gnomAD v2.1 and 0.00012% (2/1,611,936 alleles) in gnomAD v4.1, well below the PM2 threshold of 0.1%. It is absent from gnomAD-Canada. No homozygotes are observed.
gnomAD v2.1: AF=4.01e-06 (1/249196)max subpopulation AF=6.16e-05 (AFR
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently suggest a benign effect. REVEL score is 0.05 (well below pathogenic threshold), BayesDel score is -0.484 (strongly benign-tending), and SpliceAI predicts no splicing impact (max delta = 0.01). No in silico predictor suggests a deleterious effect.
REVEL: 0.05 — predicts benign (pathogenic threshold typically >0.5)BayesDel: -0.484 — strongly predicts benign (negative score)SpliceAI max delta: 0.01 — predicts no splicing alteration
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant at codon 188 with the same amino acid change (Pro188Ser) was identified.
PS2
No de novo observation was reported for this variant in any reviewed publication.
PS3
No variant-specific functional studies have been reported.
PS4
No case-control or cohort enrichment data are available for this variant.
PM1
Codon 188 (Pro188) lies outside the known critical functional domains of BARD1 (RING finger: aa 46-90; ANK repeats: aa 427-555; BRCT domains: aa 615-777).
PM6
No de novo observation with confirmed maternity and paternity has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP2
BARD1 is not established as a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3
Multiple computational predictors consistently suggest a benign effect.
PP4
No patient phenotype or family history data specific to this variant are available.
PP5
ClinVar classification for this variant is Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory), with review status of 'criteria provided, single submitter' (1-star).
Benign
BA1
The maximum observed allele frequency in any population is 0.00616% (African/African American, gnomAD v2.1), which is well below the BA1 threshold of 1%.
BS1
The maximum observed allele frequency is 0.00616% (AFR, gnomAD v2.1), well below the non-VCEP BS1 threshold of 0.3%.
BS2
No observation of this variant in a healthy adult individual has been documented for a fully penetrant disorder.
BS3
No in vitro or in vivo functional studies demonstrate a benign effect for this variant.
BS4
No segregation data are available for this variant to demonstrate lack of co-segregation with disease.
BP1
While BARD1 disease is primarily driven by loss-of-function truncating variants, pathogenic missense variants are well-documented in BARD1 (especially in the RING and BRCT domains).
BP2
No observation of this variant in trans with a known pathogenic variant has been reported.
BP5
No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6
ClinVar reports this variant as Uncertain significance (2 clinical laboratories) and Likely benign (1 clinical laboratory, Ambry Genetics), with a review status of 'criteria provided, single submitter' (1-star).
N/A · 4
PVS1 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24074e-06; MAF= 0.00012%, 2/1611936 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.6955e-06; MAF= 0.00017%, 2/1179592 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 4.01291e-06; MAF= 0.00040%, 1/249196 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15764e-05; MAF= 0.00616%, 1/16240 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,611,936
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,179,592 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 249,196
0 hom
0 hom
African/African American 1 / 16,240 |
0.0062% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 232775)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.05. BayesDel score = -0.484308.
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.
COSMIC
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
Triaged references · 8 PMIDs not cited in assessment
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
24366376 ↗
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
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
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
32866190 ↗
Gene panel screening for insight towards breast cancer susceptibility in different ethnicities.
CLINVAR
33646313 ↗
Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean.
CLINVAR