0%
BARD1c.62G>TUncertain significance
Print report
Variant interpretation report

BARD1 c.62G>T, p.(Arg21Leu)

NM_000465.4:c.62G>T NP_000456.2:p.(Arg21Leu) 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 absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% rarity threshold used for PM2 in this framework. This supports that the variant is rare in population databases.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Available computational evidence favors a benign effect for this missense change. REVEL is 0.16 and BayesDel is -0.392235, which do not support a damaging protein effect.

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.

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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 · 6 not met · 15 not assessed · 5 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.62G>T (p.Arg21Leu) variant has not been identified in a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance by a single submitter.

This variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% threshold used for PM2 and supports rarity in population databases.

Available computational evidence does not support a damaging effect, with a REVEL score of 0.16 and a BayesDel score of -0.392235, supporting benign computational evidence rather than pathogenic computational evidence.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1 (AF 0.0%), which is below the 0.1% rarity threshold used for PM2 in this framework. This supports that the variant is rare in population databases. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2 rarity threshold
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 0/1601354 alleles
  • AF 0.0%
  • homozygotes 0
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingAvailable computational evidence favors a benign effect for this missense change. REVEL is 0.16 and BayesDel is -0.392235, which do not support a damaging protein effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.16
  • BayesDel -0.392235
Still missing
  • Citable splice prediction output if additional splice assessment is needed

Not met · 6 · evaluated, threshold not reached

PM1 This variant has not been identified in a statistically significant hotspot, and available evidence does not show that codon 21 lies in a well-established critical region without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: no hotspot row found for BARD1 R21
Still missing
  • Independent evidence for a critical functional domain at this residue
Sources
hotspots ↗
PP3 Available computational evidence does not support a deleterious effect. The observed missense prediction scores are low and do not support applying pathogenic computational evidence. Details ▾Hide ▴
Evidence considered
  • REVEL 0.16
  • BayesDel -0.392235
Still missing
  • Citable splice prediction output if splicing concern remains
PP5 ClinVar reports this variant as uncertain significance rather than pathogenic or likely pathogenic, so external classification evidence does not support PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar: uncertain significance
  • criteria provided
  • single submitter
Sources
clinvar ↗PMID:25394175 ↗
BA1 Population frequency does not meet the standalone benign threshold. The variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1, which is below the 1% BA1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1 threshold
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: AF 0.0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population frequency does not support a benign interpretation. The variant is absent from gnomAD v2.1 and has 0/1,601,354 alleles in gnomAD v4.1, which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1 threshold
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: AF 0.0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP6 ClinVar does not report this variant as benign or likely benign, so external classification evidence does not support BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar: uncertain significance
  • criteria provided
  • single submitter
Sources
clinvar ↗PMID:25394175 ↗

Not assessed · 15 · no assessment recorded

PS1 No evidence was identified showing that another nucleotide change causing the same amino acid substitution, p.(Arg21Leu), has already been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • Variant-level comparison against other codon 21 substitutions with established pathogenic classifications
PS2 No confirmed de novo observation with verified maternity and paternity was identified. Details ▾Hide ▴
Still missing
  • Documented de novo testing in an affected individual
PS3 No well-established functional study showing a damaging effect of this specific variant was identified. Details ▾Hide ▴
Evidence considered
  • OncoKB has not reviewed this specific variant
Still missing
  • Validated functional assay data for BARD1 p.(Arg21Leu)
Sources
oncokb ↗
PS4 No case-control enrichment or multiple independent affected observations were identified to show that this variant is significantly increased in affected individuals over controls. Details ▾Hide ▴
Evidence considered
  • ClinVar: uncertain significance
  • single submitter
Still missing
  • Case series or case-control data establishing enrichment in affected individuals
Sources
clinvar ↗PMID:25394175 ↗
PM5 No evidence was identified showing that a different missense change at the same amino acid residue has already been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • Established pathogenic missense variants affecting BARD1 codon 21
PM6 No assumed de novo observation without confirmed parentage was identified. Details ▾Hide ▴
Still missing
  • Documented de novo occurrence data
PP1 No segregation data were identified to show that this variant tracks with disease in affected family members. Details ▾Hide ▴
Still missing
  • Family segregation studies
PP2 Available evidence does not establish that pathogenic missense variation is a common disease mechanism in BARD1 or that this gene has a low rate of benign missense variation sufficient for PP2. Details ▾Hide ▴
Still missing
  • Gene-level evidence supporting a PP2 missense mechanism
PP4 No phenotype or family history data were identified showing a highly specific clinical presentation attributable to a single genetic cause for this variant assessment. Details ▾Hide ▴
Still missing
  • Detailed phenotype and family history
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient to support a benign classification. Details ▾Hide ▴
Still missing
  • Well-documented observations in unaffected individuals with appropriate disease context
BS3 No well-established functional study showing a normal or benign effect for this specific variant was identified. Details ▾Hide ▴
Evidence considered
  • OncoKB has not reviewed this specific variant
Still missing
  • Validated benign functional assay data for BARD1 p.(Arg21Leu)
Sources
oncokb ↗
BS4 No segregation data were identified showing lack of segregation with disease. Details ▾Hide ▴
Still missing
  • Family studies demonstrating non-segregation
BP1 Available evidence does not establish that missense variants in BARD1 are generally less likely to be pathogenic than truncating variants to a degree sufficient for BP1. Details ▾Hide ▴
Evidence considered
  • BARD1 loss of function is a supported disease mechanism
Still missing
  • Gene-level evidence supporting BP1 for BARD1 missense variants
Sources
pvs1_gene_context
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a way that would support BP2. Details ▾Hide ▴
Still missing
  • Phase testing with another pathogenic variant
BP5 No alternate molecular explanation was identified for the phenotype that would support BP5. Details ▾Hide ▴
Still missing
  • Clinical context documenting an alternative established cause
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, p.(Arg21Leu), and it does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice 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 with ClinGen SVI PVS1 recommendations
Evidence considered
  • BARD1 loss of function is supported as a germline disease mechanism
  • Variant bucket: other
  • apply_generic_pvs1_framework: false
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/APM3 is used for recessive disorders when pathogenic variants are observed in trans. That evidence model is not applicable to this BARD1 hereditary cancer susceptibility evaluation. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a missense substitution and does not change protein length or create an in-frame insertion or deletion. Details ▾Hide ▴
Evidence considered
  • Protein consequence: p.(Arg21Leu)
BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Variant type: missense substitution
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is a missense substitution and BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence: p.(Arg21Leu)

Identifiers

Gene
BARD1
Transcript
NM_000465.4
Coding (HGVS c.)
NM_000465.4:c.62G>T
Protein (HGVS p.)
NP_000456.2:p.(Arg21Leu)
GRCh38
chr2:214809508 C>A
GRCh37
chr2:215674232 C>A

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 0 / 1,601,354 alleles AF 0 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,601,354 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1601354 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74788 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingAvailable computational evidence favors a benign effect for this missense change. REVEL is 0.16 and BayesDel is -0.392235, which do not support a damaging protein effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.16
  • BayesDel -0.392235
Still missing
  • Citable splice prediction output if additional splice assessment is needed
PP3 Available computational evidence does not support a deleterious effect. The observed missense prediction scores are low and do not support applying pathogenic computational evidence. Details ▾Hide ▴
Evidence considered
  • REVEL 0.16
  • BayesDel -0.392235
Still missing
  • Citable splice prediction output if splicing concern remains
BP7 N/ABP7 applies to synonymous or certain intronic variants without predicted splice impact. This variant is a missense substitution and BP7 does not apply. Details ▾Hide ▴
Evidence considered
  • Protein consequence: p.(Arg21Leu)

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.16. BayesDel score = -0.392235.

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 0 / 1,601,354 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= 0; MAF= 0.00000%, 0/1601354 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74788 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.16. BayesDel score = -0.392235.

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 previously been reported in somatic cancers (COSMIC; COSV53613702, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.