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BARD1c.764A>GUncertain significance
Print report
Variant interpretation report

BARD1 c.764A>G, p.(Asn255Ser)

NM_000465.4:c.764A>G NP_000456.2:p.(Asn255Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About BARD1

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is present at low frequency in gnomAD and remains below the non-VCEP rarity threshold of 0.1%. The highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which is below the 0.1% threshold and supports population rarity.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together support BP4.

Recorded classification: Uncertain significance

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 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

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
36 / 1,582,026 alleles

gnomAD v4.1: 36 / 1,582,026 alleles. Recorded AF 2.27556e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.16131e-05; MAF= 0.00316%, 8/253060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000327976; MAF= 0.03280%, 8/24392 alleles, homozygotes = 0); grpmax FAF= 0.00016648.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The BARD1 c.764A>G (p.Asn255Ser) variant has been reported in ClinVar predominantly as uncertain significance, with 11 uncertain significance submissions and 1 likely benign submission.

This variant is present at low frequency in population databases, with a total allele frequency of 0.00316% in gnomAD v2.1 and 0.00228% in gnomAD v4.1; the highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which remains below the 0.1% rarity threshold.

Available computational evidence is consistent with no significant functional impact, with SpliceAI predicting no significant splice effect (maximum delta score 0.04), REVEL 0.241, and BayesDel -0.546443.

Met · 2

PM2 SupportingThis variant is present at low frequency in gnomAD and remains below the non-VCEP rarity threshold of 0.1%. The highest observed population frequency is 0.03280% in gnomAD v2.1 and 0.04224% in gnomAD v4.1 in the African/African American population, which is below the 0.1% threshold and supports population rarity. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 using non-VCEP rarity threshold <0.1%
Evidence considered
  • gnomAD v2.1 total AF 0.00316%
  • highest subpopulation AF 0.03280%
  • gnomAD v4.1 total AF 0.00228%
  • highest subpopulation AF 0.04224%
Still missing
  • Gene-specific frequency thresholds were not available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together support BP4. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
  • SpliceAI max delta score 0.04
  • REVEL score 0.241
  • BayesDel score -0.546443
Sources
spliceai ↗revelbayesdel

Not met · 4 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant hotspot, and no established critical functional domain with this exact residue was identified in the available evidence. Available evidence does not support PM1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM1
Evidence considered
  • Cancer Hotspots review found no hotspot row for BARD1 residue N255
Still missing
  • No independently verified domain-specific missense clustering data were identified for residue 255.
Sources
hotspots ↗
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together do not support applying PP3. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
  • SpliceAI max delta score 0.04
  • REVEL score 0.241
  • BayesDel score -0.546443
Sources
spliceai ↗revelbayesdel
BA1 Population frequency does not reach the benign stand-alone threshold. The highest observed population frequency is 0.04224% in gnomAD v4.1, which is below the 1% BA1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1 using non-VCEP threshold >1%
Evidence considered
  • Highest observed population AF 0.04224% in gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population frequency is below the benign strong threshold. The highest observed population frequency is 0.04224% in gnomAD v4.1, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1 using non-VCEP threshold >0.3%
Evidence considered
  • Highest observed population AF 0.04224% in gnomAD v4.1
  • Highest observed population AF 0.03280% in gnomAD v2.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 15 · no assessment recorded

PS1 No confirmed pathogenic variant producing the same amino acid change, p.Asn255Ser, was identified in the available evidence. Available evidence does not support applying PS1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS1
Evidence considered
  • ClinVar includes this exact variant but no same-amino-acid pathogenic comparator was identified in the reviewed files
Still missing
  • Direct codon-level review for alternate nucleotide changes causing p.Asn255Ser was not available in the retrieved sources.
Sources
clinvar ↗
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant. Available evidence does not support applying PS2. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS2
Evidence considered
  • ClinVar summary did not provide confirmed de novo evidence
Still missing
  • No case-level inheritance data were identified.
Sources
clinvar ↗
PS3 No well-established functional study demonstrating a damaging effect of this exact variant was identified in the available evidence. Available evidence does not support applying PS3. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS3
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence
  • A cited publication was listed
  • but no assay result for this exact variant was verified in the reviewed files
Still missing
  • No validated variant-specific functional assay result was identified.
Sources
oncokb ↗PMID:23056176 ↗
PS4 This variant has been reported in ClinVar, but no case-control enrichment, odds ratio, or exact affected-carrier count sufficient for PS4 was identified. Available evidence does not support applying PS4. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS4
Evidence considered
  • ClinVar reports submissions for this variant
  • gnomAD shows the variant is present in population datasets
Still missing
  • No exact enrichment study or odds ratio for this variant was identified.
  • Case counts in affected individuals were not available in the reviewed files.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 No different pathogenic missense change at the same codon was identified in the available evidence. Available evidence does not support applying PM5. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM5
Evidence considered
  • No same-codon pathogenic comparator was identified in the available ClinVar-based materials
Still missing
  • Direct codon-level comparison data were not available in the reviewed files.
Sources
clinvar ↗
PM6 No assumed or unconfirmed de novo occurrence was identified for this variant. Available evidence does not support applying PM6. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM6
Evidence considered
  • No de novo evidence was available in the reviewed files
Still missing
  • No case-level parental testing information was identified.
Sources
clinvar ↗
PP1 No segregation data were identified for this variant. Available evidence does not support applying PP1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP1
Evidence considered
  • No segregation evidence was provided in the reviewed sources
Still missing
  • No pedigree or informative meiosis data were identified.
Sources
clinvar ↗
PP2 Available evidence does not establish that pathogenic missense variation is a sufficiently common disease mechanism in BARD1 to support PP2 for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP2
Evidence considered
  • Gene-level evidence supports loss of function
  • but no reviewed source established PP2 eligibility
Still missing
  • No gene-specific missense constraint or mechanism rule was available.
Sources
pvs1_gene_context
PP4 No phenotype or family-history information specific enough to BARD1-related disease was identified to support PP4. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP4
Evidence considered
  • No phenotype-specific data were provided
Still missing
  • Clinical phenotype details were not available.
BS2 No evidence was identified showing this variant in a number of well-phenotyped unaffected individuals sufficient for BS2. No homozygotes were observed in gnomAD. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS2
Evidence considered
  • Zero homozygotes reported in gnomAD v2.1 and v4.1
Still missing
  • No unaffected adult cohort evidence was identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional study demonstrating normal or near-normal effect for this exact variant was identified. Available evidence does not support applying BS3. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS3
Evidence considered
  • OncoKB did not identify variant-specific reviewed functional evidence
  • No verified benign functional assay result was available in the reviewed files
Still missing
  • No validated variant-specific functional assay showing preserved function was identified.
Sources
oncokb ↗PMID:23056176 ↗
BS4 No lack-of-segregation data were identified for this variant. Available evidence does not support applying BS4. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS4
Evidence considered
  • No non-segregation evidence was available in the reviewed sources
Still missing
  • No family study demonstrating non-segregation was identified.
Sources
clinvar ↗
BP1 Although loss of function is supported as a disease mechanism in BARD1, the available evidence does not establish that pathogenic missense variation is sufficiently uncommon to apply BP1 to this missense variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP1
Evidence considered
  • Gene-level evidence supports loss of function but does not by itself justify BP1
Still missing
  • No gene-specific missense-versus-truncating mechanism rule was available.
Sources
pvs1_gene_context
BP2 No co-occurrence data in trans with a pathogenic variant, or in cis in a way that would support BP2, were identified for this variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP2
Evidence considered
  • No co-occurrence information was available
Still missing
  • No phase or co-occurrence evidence was identified.
BP5 No alternate molecular explanation for the observed disease in an affected individual was identified in the available evidence. Available evidence does not support applying BP5. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP5
Evidence considered
  • No alternate-cause evidence was provided
Still missing
  • No case-level genotype and phenotype context was available.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, c.764A>G (p.Asn255Ser), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although loss of function is an established disease mechanism for BARD1, available evidence does not support applying PVS1 to this specific variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI PVS1 fallback
Evidence considered
  • BARD1 loss of function is eligible for generic PVS1 consideration at the gene level
  • c.764A>G is not a null variant and is not a canonical splice-site change
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 is intended for recessive disorders with trans observations. No recessive application was identified for this BARD1 hereditary cancer interpretation. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM3
Evidence considered
  • Generic ACMG recessive trans criterion not applicable to this review context
PM4 N/AThis variant is a missense substitution and does not cause a protein length change. PM4 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM4
Evidence considered
  • Protein consequence is p.Asn255Ser missense
PP5 N/APP5 is not applied because external assertions without independently reviewable evidence are not used for current ACMG/AMP interpretation. Details ▾Hide ▴
Rule
PP5 not used in current ACMG/AMP practice
Evidence considered
  • ClinVar assertions were reviewed but not used as standalone evidence under PP5
Sources
clinvar ↗
BP3 N/AThis variant is not an in-frame deletion or insertion in a repetitive region. BP3 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP3
Evidence considered
  • Protein consequence is missense
  • not in-frame indel
BP6 N/ABP6 is not applied because external benign assertions without independently reviewable evidence are not used as standalone evidence in current ACMG/AMP interpretation. Details ▾Hide ▴
Rule
BP6 not used in current ACMG/AMP practice
Evidence considered
  • A single ClinVar likely benign submission was reviewed but not used as standalone BP6 evidence
Sources
clinvar ↗
BP7 N/AThis variant is a missense substitution and not a synonymous or deep intronic change. BP7 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
  • Protein consequence is p.Asn255Ser missense

Identifiers

Gene
BARD1
Transcript
NM_000465.4
Coding (HGVS c.)
NM_000465.4:c.764A>G
Protein (HGVS p.)
NP_000456.2:p.(Asn255Ser)
GRCh38
chr2:214781110 T>C
GRCh37
chr2:215645834 T>C

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…
gnomAD v4.1 36 / 1,582,026 alleles AF 2.28e-05 · 0 homozygotes · FAF 0.000306
gnomAD v2.1 8 / 253,060 alleles AF 3.16e-05 · 0 homozygotes · FAF 0.000166

By genetic ancestry

gnomAD v4.1

AF 2.3e-05 · 36 / 1,582,026 alleles · 0 hom · FAF 0.00031
African/African American31 / 73,396 0.00042
Admixed American4 / 54,192 7.4e-05
Remaining individuals1 / 60,992 1.6e-05
0 alternate alleles recorded in 7 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

gnomAD v2.1

AF 3.2e-05 · 8 / 253,060 alleles · 0 hom · FAF 0.00017
African/African American8 / 24,392 0.00033
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.27556e-05; MAF= 0.00228%, 36/1582026 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000422366; MAF= 0.04224%, 31/73396 alleles, homozygotes = 0); grpmax FAF= 0.00030571.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.16131e-05; MAF= 0.00316%, 8/253060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000327976; MAF= 0.03280%, 8/24392 alleles, homozygotes = 0); grpmax FAF= 0.00016648.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational results support no damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together support BP4. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP4
Evidence considered
  • SpliceAI max delta score 0.04
  • REVEL score 0.241
  • BayesDel score -0.546443
Sources
spliceai ↗revelbayesdel
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, REVEL is 0.241, and BayesDel is -0.546443, which together do not support applying PP3. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP3
Evidence considered
  • SpliceAI max delta score 0.04
  • REVEL score 0.241
  • BayesDel score -0.546443
Sources
spliceai ↗revelbayesdel
BP7 N/AThis variant is a missense substitution and not a synonymous or deep intronic change. BP7 does not apply. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
  • Protein consequence is p.Asn255Ser missense

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.241. BayesDel score = -0.546443.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 36 / 1,582,026 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record 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

This variant is present in gnomAD v4.1 (AF= 2.27556e-05; MAF= 0.00228%, 36/1582026 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000422366; MAF= 0.04224%, 31/73396 alleles, homozygotes = 0); grpmax FAF= 0.00030571.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.16131e-05; MAF= 0.00316%, 8/253060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000327976; MAF= 0.03280%, 8/24392 alleles, homozygotes = 0); grpmax FAF= 0.00016648.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.241. BayesDel score = -0.546443.

Functional

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.