BARD1c.1694G>ALikely benign

Print report

Variant interpretation report

BARD1 c.1694G>A, p.(Arg565His)

NM_000465.4:c.1694G>A NP_000456.2:p.(Arg565His) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BARD1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (benign) · 2 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 10 Likely benign · 4 Uncertain significance · 2 Benign · 1 Likely Benign · 1 benign
Pipeline record: 15 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

BS2 (supporting): Observed in the homozygous state in 3 individuals in gnomAD v4.1, a general population database. BARD1 is a tumor suppressor gene where biallelic loss-of-function would be expected to have significant phenotypic consequences. The observation of homozygosity in presumably healthy population controls suggests the variant is tolerated even in the homozygous state.
BS3 (strong): Direct functional testing of BARD1 R565H in a validated homology-directed repair (HDR) assay demonstrated unequivocally normal function. Adamovich et al. (PMID:30925164) tested 76 BARD1 missense variants in a well-characterized HDR assay that accurately discriminates known pathogenic from known benign BARD1 variants. R565H was proficient in HDR with activity comparable to wild-type and was explicitly grouped with other functional variants that were interpreted as 'likely benign.' The HDR assay has been validated as predictive of BRCA1/BARD1 pathogenicity, with truncating variants and known pathogenic missense variants showing HDR deficiency while known benign variants remain functional.
BP4 (supporting): Multiple lines of computational evidence support a benign effect. REVEL score is 0.179 (well below damaging thresholds). BayesDel score is -0.24551 (negative, supporting benign). SpliceAI max delta score is 0.01 (no predicted splicing impact). The preponderance of in silico evidence from validated ensemble predictors supports a benign interpretation, consistent with the functional data showing normal HDR activity.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3

BS2Supporting

BS2 · supporting

Observed in the homozygous state in 3 individuals in gnomAD v4.1, a general population database. BARD1 is a tumor suppressor gene where biallelic loss-of-function would be expected to have significant phenotypic consequences. The observation of homozygosity in presumably healthy population controls suggests the variant is tolerated even in the homozygous state.

BS3Strong

BS3 · strong

Direct functional testing of BARD1 R565H in a validated homology-directed repair (HDR) assay demonstrated unequivocally normal function. Adamovich et al. (PMID:30925164) tested 76 BARD1 missense variants in a well-characterized HDR assay that accurately discriminates known pathogenic from known benign BARD1 variants. R565H was proficient in HDR with activity comparable to wild-type and was explicitly grouped with other functional variants that were interpreted as 'likely benign.' The HDR assay has been validated as predictive of BRCA1/BARD1 pathogenicity, with truncating variants and known pathogenic missense variants showing HDR deficiency while known benign variants remain functional.

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence support a benign effect. REVEL score is 0.179 (well below damaging thresholds). BayesDel score is -0.24551 (negative, supporting benign). SpliceAI max delta score is 0.01 (no predicted splicing impact). The preponderance of in silico evidence from validated ensemble predictors supports a benign interpretation, consistent with the functional data showing normal HDR activity.

Recorded classification: Likely 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: BS2 supporting benign, BS3 strong benign, BP4 supporting benign; combination = 1 strong benign + 2 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

340 / 1,614,046 alleles

gnomAD v4.1: 340 / 1,614,046 alleles. Recorded AF 0.000210651. Recorded homozygote count 3.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.0003714; MAF= 0.03714%, 105/282714 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00222135; MAF= 0.22214%, 68/30612 alleles, homozygotes = 0); grpmax FAF= 0.00179691.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · BS2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

18 reported laboratory submissions

10 Likely benign · 4 Uncertain significance · 2 Benign · 1 Likely Benign · 1 benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗

Functional evidence

Statement recorded

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.

Applied · BS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99640229, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 20 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

BARD1 c.1694G>A (p.Arg565His) is a missense variant in exon 8 located in the inter-domain region between the ankyrin repeat and BRCT domains.

Direct functional testing in a validated homology-directed repair (HDR) assay demonstrated that BARD1 R565H is fully functional, with HDR activity comparable to wild-type. The variant was explicitly classified as 'functional in HDR' alongside known benign variants (PMID:30925164).

This variant is present in gnomAD v2.1 at 105/282,714 alleles (AF=0.037%) and in gnomAD v4.1 at 340/1,614,046 alleles (AF=0.021%), with 3 homozygous individuals observed in v4.1. Homozygosity in a general population database is inconsistent with a highly penetrant pathogenic variant in a tumor suppressor gene.

Multiple in silico tools support a benign effect: REVEL score 0.179, BayesDel score -0.24551, and SpliceAI max delta 0.01 (no splicing impact).

ClinVar reports this variant as Likely benign based on submissions from 10 clinical laboratories, with an additional 2 laboratories reporting Benign and 4 reporting Uncertain significance (Variation ID 127721).

The variant was observed in 1 of 354 sporadic breast cancer cases and 0 of 258 controls (PMID:17972171), which does not establish significant case enrichment. A single FCCTX colorectal cancer case carrying this variant has also been reported, but colorectal cancer is not within the primary BARD1-associated disease spectrum (PMID:32984025).

No evidence of de novo occurrence, co-segregation with disease, or location within a critical functional domain or mutational hotspot was identified. Residue 565 lies in a linker region where variants tested in functional studies were generally proficient in DNA repair.

Met · 3

BS2 SupportingObserved in the homozygous state in 3 individuals in gnomAD v4.1, a general population database. BARD1 is a tumor suppressor gene where biallelic loss-of-function would be expected to have significant phenotypic consequences. The observation of homozygosity in presumably healthy population controls suggests the variant is tolerated even in the homozygous state. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 3 homozygous individuals observed among 340 total allele counts.
Homozygosity in a general population database is inconsistent with a highly penetrant pathogenic variant.

Still missing

Phenotype data for the 3 homozygous individuals are not available
they are assumed to be healthy population controls.

Sources

gnomad_v4 ↗

BS3 StrongDirect functional testing of BARD1 R565H in a validated homology-directed repair (HDR) assay demonstrated unequivocally normal function. Adamovich et al. (PMID:30925164) tested 76 BARD1 missense variants in a well-characterized HDR assay that accurately discriminates known pathogenic from known benign BARD1 variants. R565H was proficient in HDR with activity comparable to wild-type and was explicitly grouped with other functional variants that were interpreted as 'likely benign.' The HDR assay has been validated as predictive of BRCA1/BARD1 pathogenicity, with truncating variants and known pathogenic missense variants showing HDR deficiency while known benign variants remain functional. Details ▾Hide ▴

Evidence considered

HDR assay in HeLa-DR cells: BARD1 R565H showed normal HDR function
comparable to wild-type.
R565H was explicitly listed among variants 'which were functional in HDR' and grouped with likely benign variants.
The HDR assay correctly classified known pathogenic truncating variants (V154fs
S551*
Q564*) as non-functional and known benign variants (S241C
E361D) as functional.
Authors concluded: 'Since these variants were functional in the HDR assay
we would interpret such variants as likely benign.'

Sources

PMID:30925164 ↗

BP4 SupportingMultiple lines of computational evidence support a benign effect. REVEL score is 0.179 (well below damaging thresholds). BayesDel score is -0.24551 (negative, supporting benign). SpliceAI max delta score is 0.01 (no predicted splicing impact). The preponderance of in silico evidence from validated ensemble predictors supports a benign interpretation, consistent with the functional data showing normal HDR activity. Details ▾Hide ▴

Evidence considered

REVEL score: 0.179 (benign).
BayesDel score: -0.24551 (negative
supporting benign).
SpliceAI max delta: 0.01 (no predicted splicing impact).

Sources

revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at codon 565 resulting in the same amino acid substitution (p.Arg565His) that has been classified as pathogenic. PM5 candidate harvesting found no eligible comparators at this residue. Details ▾Hide ▴

Evidence considered

No alternate nucleotide change producing p.Arg565His with a pathogenic classification was identified.

Sources

pm5_candidates

PS2 No de novo observation with confirmed maternity and paternity has been reported for this variant in any reviewed publication or database. Details ▾Hide ▴

Evidence considered

No de novo data available in ClinVar
literature
or population databases.

Still missing

De novo testing not performed for this variant in any reviewed study.

PS3 Direct functional testing of BARD1 R565H in a validated homology-directed repair (HDR) assay demonstrated that the variant is functional and proficient in DNA repair, comparable to wild-type. The variant was explicitly classified among 'functional in HDR' variants alongside known benign variants (PMID:30925164). This functional evidence contradicts a damaging effect and instead supports a benign interpretation. Details ▾Hide ▴

Evidence considered

HDR assay in HeLa-DR cells: BARD1 R565H was proficient in homology-directed repair
with activity comparable to wild-type.
Adamovich et al. 2019 explicitly list R565H among variants that 'were functional in HDR.'

Sources

PMID:30925164 ↗

PS4 Observed in 1 of 354 sporadic breast cancer cases and 0 of 258 controls (PMID:17972171), which does not establish statistically significant enrichment. The variant is present in gnomAD at 105/282,714 alleles (v2.1, AF=0.037%) and 340/1,614,046 alleles (v4.1, AF=0.021%), indicating it is established in the general population at frequencies incompatible with a highly penetrant pathogenic variant. No case-control study demonstrates significant enrichment in affected individuals. Details ▾Hide ▴

Evidence considered

1/354 sporadic breast cancer cases vs 0/258 controls (PMID:17972171)
not statistically significant.
gnomAD v2.1: 105/282
714 alleles (AF=0.037%).
gnomAD v4.1: 340/1
614
046 alleles (AF=0.021%).

Still missing

No adequately powered case-control study exists for this variant.

Sources

gnomad_v2 ↗gnomad_v4 ↗PMID:17972171 ↗

PM1 Residue Arg565 lies in the inter-domain region between the ankyrin repeat domain (residues 427-525) and the first BRCT domain (residues 616-653). It is not located within a well-characterized critical functional domain. Cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. Functional data (PMID:30925164) shows variants in this inter-domain region are proficient in DNA repair, further arguing against a critical domain assignment. Details ▾Hide ▴

Evidence considered

Arg565 is in the inter-domain linker between ankyrin repeats and BRCT domains
not within a defined functional domain.
Cancerhotspots.org: residue not significant
exact variant not listed.
PMID:30925164: variants between ankyrin and BRCT domains were proficient in HDR
with R565C being the only exception (borderline).

Sources

PMID:30925164 ↗PMID:23056176 ↗

PM2 Although total allele frequency in gnomAD v2.1 is 0.037% (below 0.1% PM2 threshold), the variant is present at 105 alleles in v2.1 and 340 alleles in v4.1 with 3 homozygous individuals observed in v4.1. The presence of homozygotes in a general population database and occurrence across multiple continental populations indicates this variant is established in the population and does not meet the 'absent from controls' standard of PM2. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 105/282
714 alleles (AF=0.037%)
0 homozygotes.
gnomAD v4.1: 340/1
614
046 alleles (AF=0.021%)
3 homozygotes.
South Asian subpopulation AF=0.22% (v2.1)
Ashkenazi Jewish AF=0.14% (v2.1).

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM5 No known pathogenic missense variant at codon 565 with a different amino acid change has been established. R565C was tested in the HDR functional assay (PMID:30925164) and showed borderline activity just below the 0.6 cutoff, but it is not classified as pathogenic in ClinVar and does not satisfy the PM5 requirement for an established pathogenic comparator at the same residue. Details ▾Hide ▴

Evidence considered

PM5 candidate harvesting found no eligible pathogenic comparators at codon 565.
R565C had borderline HDR activity (just below 0.6 cutoff) but is not classified as pathogenic in ClinVar.

Sources

pm5_candidatesPMID:30925164 ↗

PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for this variant in any reviewed source. Details ▾Hide ▴

Evidence considered

No de novo data available.

Still missing

No de novo testing reported for this variant.

PP1 No co-segregation data are available. The variant was reported in a single sporadic breast cancer case (PMID:17972171) without family studies, and in a single FCCTX colorectal cancer case (PMID:32984025) without segregation analysis. The Gorringe et al. study specifically tested segregation of other BARD1 variants but did not analyze R565H for segregation. Details ▾Hide ▴

Evidence considered

Single sporadic breast cancer case (PMID:17972171)
no family segregation data.
Single FCCTX colorectal cancer case (PMID:32984025)

Still missing

No co-segregation analysis performed for this variant.

Sources

PMID:17972171 ↗PMID:32984025 ↗

PP2 BARD1 has a high rate of benign missense variation. Multiple common missense polymorphisms have been documented including P24S, M507V, C557S, and I738V (PMID:17972171). The gene does not exhibit a low rate of benign missense variation, and pathogenic missense variants are also well-documented (PMID:30925164), indicating missense changes are not inherently pathogenic in this gene. Details ▾Hide ▴

Evidence considered

BARD1 harbors numerous benign missense polymorphisms (P24S
M507V
C557S
I738V).
Both benign and pathogenic missense variants are documented in BARD1.

Sources

PMID:17972171 ↗PMID:30925164 ↗

PP3 Multiple in silico tools predict a benign effect. REVEL score is 0.179 (well below the typical ≥0.5 damaging threshold). BayesDel score is -0.24551 (negative, supporting a benign interpretation). SpliceAI delta score is 0.01 (no predicted splicing impact). Although PolyPhen predicted damaging in an earlier in silico screen (PMID:23056176), the preponderance of evidence from validated ensemble predictors (REVEL, BayesDel) supports a benign computational profile. Details ▾Hide ▴

Evidence considered

REVEL score: 0.179 (benign range).
BayesDel score: -0.24551 (negative
supporting benign).
SpliceAI max delta: 0.01 (no splicing impact predicted).
PolyPhen (PMID:23056176): predicted damaging with PSIC 1.859
SIFT in the same study did not predict deleterious.

Sources

revelbayesdelspliceai ↗PMID:23056176 ↗

PP4 The variant has been observed in a colorectal cancer case (FCCTX, PMID:32984025) and a sporadic breast cancer case (PMID:17972171). The colorectal cancer phenotype is not within the primary BARD1-associated disease spectrum (hereditary breast and ovarian cancer). No specific phenotypic data or family history highly specific for BARD1-related disease is available for either proband. Details ▾Hide ▴

Evidence considered

Observed in a 68-year-old female with ascending and sigmoid colon cancer (FCCTX
PMID:32984025).
Observed in a single sporadic breast cancer case (PMID:17972171).
No phenotype highly specific for BARD1-related hereditary breast/ovarian cancer documented.

Still missing

Detailed phenotype and family history of probands not available.

Sources

PMID:17972171 ↗PMID:32984025 ↗

PP5 ClinVar review status for this variant is 'criteria provided, single submitter' (1-star). Per adjudication rules, PP5 applies at supporting strength only for 3-star expert panel submissions. No expert panel (CSPEC/VCEP or ClinGen) has reviewed this variant. The overall ClinVar classification is Likely benign, which would support BP6 rather than PP5. Details ▾Hide ▴

Evidence considered

ClinVar classification: Likely benign
review status 1-star (Variation ID 127721). No expert panel review.

Sources

clinvar ↗

BA1 Allele frequency in gnomAD v2.1 is 0.037% (total) with maximum subpopulation frequency 0.22% (South Asian). In gnomAD v4.1, total AF is 0.021% with max subpopulation AF 0.17% (South Asian). All frequencies are far below the 1% BA1 threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 total AF: 0.037% (far below 1% BA1 threshold).
gnomAD v4.1 total AF: 0.021%.
Maximum subpopulation AF (South Asian): 0.22% (v2.1).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Allele frequency in gnomAD v2.1 is 0.037% (total), which is below the 0.3% BS1 threshold (non-VCEP). The maximum subpopulation frequency in South Asians is 0.22%, also below the threshold. Grpmax FAF in v2.1 is 0.18%, also below 0.3%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 total AF: 0.037% (<0.3% BS1 threshold).
Max subpopulation AF: 0.22% (South Asian
v2.1).
Grpmax FAF: 0.18% (v2.1).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS4 No co-segregation data are available for this variant. While the Gorringe et al. study (PMID:17972171) tested segregation for other BARD1 variants (T598I, I692T) and found no segregation with disease, R565H was identified in a single sporadic case and was not included in segregation analysis. Details ▾Hide ▴

Evidence considered

R565H was not tested for co-segregation in the only study with pedigree data (PMID:17972171).

Still missing

No co-segregation analysis available for this variant.

Sources

PMID:17972171 ↗

BP2 No data are available regarding observation of this variant in trans with a known pathogenic variant in BARD1. Details ▾Hide ▴

Evidence considered

No trans phase data available.

Still missing

Observation in trans with pathogenic variant not assessed.

BP5 No data are available demonstrating that a case carrying this variant has an alternate molecular basis for disease. The variant was observed in an FCCTX patient (PMID:32984025) who also carried BRCA2 variants, but these were classified as VUS and do not constitute an alternate definitive molecular diagnosis. Details ▾Hide ▴

Evidence considered

FCCTX case carrying R565H also had BRCA2 VUS (PMID:32984025)
which does not represent an alternate definitive molecular diagnosis.

Still missing

No cases with an alternate definitive molecular cause identified.

Sources

PMID:32984025 ↗

BP6 Although ClinVar reports this variant as Likely benign with strong clinical laboratory consensus (10 labs reporting Likely benign, 2 reporting Benign, 4 reporting VUS), the review status is 'criteria provided, single submitter' (1-star). Per adjudication rules, BP6 applies at supporting strength only for 3-star expert panel submissions. No ClinGen or VCEP expert panel has reviewed this variant. Details ▾Hide ▴

Evidence considered

ClinVar consensus: Likely benign (10 LB + 2 B + 4 VUS + 1 LB + 1 benign submissions).
Review status: 1-star (criteria provided
single submitter). No expert panel review.

Still missing

No expert panel review of this variant.

Sources

clinvar ↗

PS5 No reputable source classifies this variant as pathogenic. ClinVar consensus classification is Likely benign (10 clinical laboratories reporting Likely benign, 2 reporting Benign). No expert panel has reviewed this variant. Details ▾Hide ▴

Evidence considered

ClinVar classification: Likely benign (Variation ID 127721). No pathogenic submissions from reputable sources.

Sources

clinvar ↗

Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant (c.1694G>A, p.Arg565His). PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). The variant does not fall into any of the default generic PVS1 null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴

Evidence considered

Missense substitution at codon 565 does not qualify for PVS1 null-variant framework.

Sources

pvs1_generic_framework ↗

PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. BARD1-associated disease is autosomal dominant; PM3 is not applicable in this context. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes (in-frame deletions/insertions, stop-loss). This is a single-nucleotide missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. In BARD1, both truncating and missense variants are established mechanisms of disease. Multiple missense variants in BARD1 have been demonstrated to be HDR-deficient and are classified as pathogenic (PMID:30925164). Therefore, a missense change in BARD1 cannot be assumed benign solely on the basis of variant type. Details ▾Hide ▴

Evidence considered

BARD1 has both truncating and missense pathogenic variants
missense is an established disease mechanism.

Sources

PMID:30925164 ↗

BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.1694G>A, p.Arg565His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
BP7 is for synonymous variants only.

Identifiers

Gene: BARD1
Transcript: NM_000465.4
Coding (HGVS c.): NM_000465.4:c.1694G>A
Protein (HGVS p.): NP_000456.2:p.(Arg565His)
GRCh38: chr2:214745838 C>T
GRCh37: chr2:215610562 C>T
ClinVar: 127721
COSMIC: COSV99640229

Gene diagram

Every interpreted variant in BARD1, mapped onto the exon structure of NM_000465.4. Select a row to find it on the plot.

BARD1NM_000465.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in BARD1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 340 / 1,614,046 alleles AF 0.000211 · 3 homozygotes · FAF 0.00152

gnomAD v2.1 105 / 282,714 alleles AF 0.000371 · 0 homozygotes · FAF 0.0018

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00021 · 340 / 1,614,046 alleles · 3 hom · FAF 0.0015

South Asian159 / 91,078	0.00172 hom
Middle Eastern9 / 6,060	0.0015
Ashkenazi Jewish31 / 29,600	0.001
Remaining individuals30 / 62,504	0.000481 hom
East Asian4 / 44,854	8.9e-05
European (non-Finnish)102 / 1,179,982	8.6e-05
Admixed American3 / 60,018	5e-05
African/African American2 / 75,034	2.7e-05

0 alternate alleles recorded in 2 other groups: European (Finnish), Amish.

gnomAD v2.1

AF 0.00037 · 105 / 282,714 alleles · 0 hom · FAF 0.0018

South Asian68 / 30,612	0.0022
Ashkenazi Jewish14 / 10,366	0.0014
Remaining individuals1 / 7,210	0.00014
European (non-Finnish)16 / 129,066	0.00012
East Asian2 / 19,952	0.0001
Admixed American3 / 35,438	8.5e-05
African/African American1 / 24,964	4e-05

0 alternate alleles recorded in 1 other group: European (Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000210651; MAF= 0.02107%, 340/1614046 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00174576; MAF= 0.17458%, 159/91078 alleles, homozygotes = 2); grpmax FAF= 0.00152378.

gnomAD v2.1

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +16 bp

0.010

SpliceAI acceptor gainat -27 bp

0.000

SpliceAI donor lossat -116 bp

0.000

SpliceAI donor gainat +16 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: 0.179
BayesDel: -0.246

How the predictions were used

Evidence considered

REVEL score: 0.179 (benign).
BayesDel score: -0.24551 (negative
supporting benign).
SpliceAI max delta: 0.01 (no predicted splicing impact).

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL score: 0.179 (benign range).
BayesDel score: -0.24551 (negative
supporting benign).
SpliceAI max delta: 0.01 (no splicing impact predicted).
PolyPhen (PMID:23056176): predicted damaging with PSIC 1.859
SIFT in the same study did not predict deleterious.

Sources

revelbayesdelspliceai ↗PMID:23056176 ↗

BP7 N/AThis is a missense variant (c.1694G>A, p.Arg565His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.179. BayesDel score = -0.24551.

9 paper records listed. 1 cited in the classification.

Cited in the classification

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.

Adamovich AI et al. · 2019 Mar

BARD1 R565H was directly tested in a validated homology-directed repair (HDR) functional assay in HeLa-DR cells alongside 75 other BARD1 missense variants. R565H was proficient in HDR with activity comparable to wild-type and was explicitly grouped among 'functional in HDR' variants. The authors interpreted HDR-functional variants as 'likely benign,' noting that this interpretation is consistent with ClinVar classifications where known pathogenic variants are HDR-deficient and known benign variants are HDR-functional.
→ BS3 Names this variant
PMID 30925164 ↗
Source detail

The variants V85L, R194K, I258T, N326S, R565H, and R641Q, which were functional in HDR, have conflicting reports of pathogenicity, with reports indicating they were VUS or likely benign. Since these variants were functional in the HDR assay, we would interpret such variants as likely benign.

Location Results section, 'Analysis of BARD1 variants in Homology-Directed Repair (HDR)'; Discussion section

Context Homology-directed repair (HDR) assay in HeLa-DR cells; endogenous BARD1 depleted by siRNA, variant BARD1 expressed from plasmid; flow cytometry readout of GFP-positive cells.

Other recorded publications

BARD1 variants are not associated with breast cancer risk in Australian familial breast cancer.

Gorringe KL et al. · 2008

G1767A (Arg565His) was identified as a novel nonsynonymous variant in 1 of 354 sporadic breast cancer cases and was absent from 258 non-cancer controls. The Arg565 residue is conserved in mouse Bard1, but the significance of this variant was reported as unclear and it was not investigated further. No segregation analysis was performed for this variant.
Names this variant
PMID 17972171 ↗
Quoted passage
We identified a novel non-synonymous sequence variant G1767A (Arg565His) in a single sporadic breast cancer case but not in any of 258 non-cancer controls. The Arg565 residue is conserved in the mouse Bard1 sequence, however, the significance of this variant is unclear and it was not investigated further.
Results and discussion, Table 2, line 'G1767A Arg565His'
Identification of functional SNPs in BARD1 gene and in silico analysis of damaging SNPs: based on data procured from dbSNP database.

Alshatwi AA et al. · 2012

This in silico study analyzed 50 nonsynonymous SNPs in BARD1 from the dbSNP database. rs146946984 (Arg565His, corresponding to c.1694G>A) was predicted damaging by PolyPhen (PSIC score 1.859) but was not predicted deleterious by SIFT. The variant was noted as having been studied in previous populations and was one of several SNPs 'recorded in the dbSNP database for the BARD1 gene,' but no novel functional or clinical data were generated for this variant.
Names this variant
PMID 23056176 ↗
Quoted passage
rs146946984 (Arg565His) has been predicted to be deleterious by PolyPhen only.
Results and Discussion, Table 2, and Discussion section
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.

This is the ACMG/AMP standards and guidelines for the interpretation of sequence variants. It provides the classification framework and criteria definitions but does not mention NM_000465.4:c.1694G>A or any BARD1-specific variant.
Does not name this variant
PMID 25741868 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

This paper describes a standardized DNA variant scoring system for Mendelian disorders. It does not mention NM_000465.4:c.1694G>A, BARD1, or any variant-specific data relevant to this adjudication.
Does not name this variant
PMID 26467025 ↗
Comparison Between Familial Colorectal Cancer Type X and Lynch Syndrome: Molecular, Clinical, and Pathological Characteristics and Pedigrees.

Xu Y et al. · 2020

BARD1 c.1694G>A (p.Arg565His, NC_000002.11:g.215610562C>T) was detected in one FCCTX (familial colorectal cancer type X) patient, a 68-year-old female with ascending and sigmoid colon cancer. The variant was classified as a VUS. The same patient also carried two BRCA2 VUS. The study compared molecular and clinical characteristics of FCCTX versus Lynch syndrome; this variant was incidental to the study's primary aim.
Names this variant
PMID 32984025 ↗
Quoted passage
BARD1 NC_000002.11:g.215610562C>T(p. Arg565His) SNV VUS
Table 1, 'Detected mutations in the 27 patients of the FCCTX group'
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.

GeneReviews entry for BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. No abstract or full text available for review. This resource focuses on BRCA1/2 and is unlikely to contain variant-specific information for BARD1 c.1694G>A.
Does not name this variant
PMID 20301425 ↗
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.

This is the USPSTF recommendation statement on risk assessment, genetic counseling, and genetic testing for BRCA-related cancer. It focuses on BRCA1/BRCA2 testing and does not mention BARD1 or NM_000465.4:c.1694G>A.
Does not name this variant
PMID 24366376 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Sherloc classification criteria refinement paper. No full text available. This is a background methodology paper and is not expected to contain variant-specific data for BARD1 c.1694G>A.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 340 / 1,614,046 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗

ClinVar 10 Likely benign · 4 Uncertain significance · 2 Benign · 1 Likely Benign · 1 benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 127721)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.179. BayesDel score = -0.24551.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99640229, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.