About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.6859A>T, p.(Arg2287Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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 ClinGen BRCA2 VCEP v1.2.0. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change, NM_000059.3:c.6859A>T (p.Arg2287Ter), in BRCA2, a gene in which loss of function is an established disease mechanism. The ENIGMA BRCA2 exon-level table assigns PVS1 to protein-truncating variants in exon 12; this variant lies in exon 12.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override) applied to the authoritative adjudicated criteria.
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
1 / 1,556,108 alleles
gnomAD v4.1: 1 / 1,556,108 alleles. Recorded AF 6.42629e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 9 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BRCA2 c.6859A>T (p.Arg2287Ter; p.R2287*) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic with expert panel review.
This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), consistent with extreme rarity.
Under the ENIGMA BRCA2 specification, this exon 12 premature termination variant is a null variant in a gene where loss of function is an established disease mechanism, and the exon-level table assigns PVS1 to protein-truncating variants in exon 12.
SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which does not support PP3 for splice disruption.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a nonsense change, NM_000059.3:c.6859A>T (p.Arg2287Ter), in BRCA2, a gene in which loss of function is an established disease mechanism. The ENIGMA BRCA2 exon-level table assigns PVS1 to protein-truncating variants in exon 12; this variant lies in exon 12. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 for null variants; exon-level Table 4 assigns PVS1 to exon 12 PTC variants.
Evidence considered
- Protein consequence is p.(Arg2287Ter).
- Variant maps to exon 12.
- BRCA2 exon 12 PTC row is annotated PVS1 in the ENIGMA table.
Still missing
- The exon 12 notes indicate that intermediate-risk effects should not be disregarded and merit expert confirmation in the final review.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 4 · evaluated, threshold not reached
PS1 No previously classified variant with the same proven protein change or the same established splice effect was identified for this variant. This change is a nonsense variant, and available splice prediction does not show a pathogenic-equivalent splice effect. Details ▾Hide ▴
Rule
PS1 requires the same established amino-acid change or equivalent splice effect as a previously classified pathogenic variant.
Evidence considered
- SpliceAI max delta score is 0.10.
- No same-amino-acid substitution evidence was identified.
Still missing
- A direct BRCA2 Table 5 comparison set was not retrieved in the available materials.
Sources
PM2 Available population data do not show complete absence from controls. The variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), so the ENIGMA absence requirement is not fully satisfied. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from controls.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 1 allele
- AF 6.426289177871973e-07
- 0 homozygotes.
Still missing
- A gnomAD v3.1-specific lookup was not retrieved in the available materials.
Sources
BA1 Population frequency is far below the ENIGMA BA1 threshold. In gnomAD v4.1 the variant is present at 1/1,556,108 alleles (AF 6.43e-07; 0.000064%), which is well below the BA1 threshold of greater than 0.1%. Details ▾Hide ▴
Rule
BA1 requires filter allele frequency greater than 0.001 (0.1%).
Evidence considered
- gnomAD v4.1 total AF 6.426289177871973e-07.
Sources
BS1 Population frequency is far below the ENIGMA BS1 thresholds. In gnomAD v4.1 the highest observed population frequency is 8.85e-07 (0.000089%) in European non-Finnish individuals, which is below the BS1 supporting threshold of greater than 0.00002 and far below the strong threshold of greater than 0.0001. Details ▾Hide ▴
Rule
BS1 requires elevated filter allele frequency above BRCA2 ENIGMA thresholds.
Evidence considered
- Best observed subpopulation AF 8.849025014423911e-07 in NFE.
Still missing
- Filter allele frequency values were not available in the retrieved record.
Sources
Not assessed · 9 · no assessment recorded
PS3 No variant-specific calibrated functional assay result supporting a damaging effect was identified in the reviewed ENIGMA functional table for this variant. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies showing a damaging effect.
Evidence considered
- No exact NM_000059.3:c.6859A>T or p.Arg2287Ter entry was identified in ENIGMA Table 9.
- OncoKB points to curated literature context but does not itself provide a calibrated ENIGMA PS3 assignment for this variant.
Still missing
- Direct review of any cited primary functional papers would be needed if additional variant-specific assay data emerge.
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PS4 No case-control enrichment result or quantitative affected-versus-control evidence meeting ENIGMA PS4 requirements was identified for this variant. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- No exact variant match was identified in the reviewed ENIGMA posterior-probability and multifactorial lookup resources.
Still missing
- No direct case-control dataset or multifactorial PS4-supporting row for this exact variant was identified in the reviewed BRCA2 resources.
Sources
PM3 No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia. Details ▾Hide ▴
Rule
PM3 in BRCA2 is reserved for specific Fanconi anemia contexts with point-based scoring.
Evidence considered
- No PM3-compatible proband data were identified.
Still missing
- No phenotype-specific Fanconi anemia case data were identified.
Sources
PP1 No segregation data were identified showing that this variant tracks with disease in affected relatives. Details ▾Hide ▴
Rule
PP1 requires quantitative cosegregation evidence.
Evidence considered
- No quantitative cosegregation evidence was retrieved.
Still missing
- No informative family-based likelihood ratio or pedigree data were identified.
Sources
PP4 No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified. Review of the BRCA2 clinical-history likelihood-ratio workbook did not find an exact entry for this variant. Details ▾Hide ▴
Rule
PP4 in BRCA2 requires a quantitative multifactorial clinical-history LR of at least 2.08.
Evidence considered
- No exact NM_000059.3:c.6859A>T / HGVS_Nucleotide match was identified in the BRCA2 LR workbook.
Still missing
- No exact HGVS match was identified in the reviewed BRCA2 clinical-history LR resource.
Sources
BS2 No data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in the point-based framework required for BRCA2 BS2. Details ▾Hide ▴
Rule
BS2 in BRCA2 uses a Fanconi anemia-based point system.
Evidence considered
- No qualifying BRCA2 BS2 evidence was retrieved.
Still missing
- No BS2 point-based proband data were identified.
Sources
BS3 No variant-specific calibrated functional assay result showing no damaging effect was identified in the reviewed ENIGMA functional table for this variant. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- No exact NM_000059.3:c.6859A>T or p.Arg2287Ter entry was identified in ENIGMA Table 9.
Still missing
- Direct review of any primary benign functional studies would be needed if additional variant-specific assay data emerge.
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 No nonsegregation data were identified showing that this variant fails to track with disease in affected relatives. Details ▾Hide ▴
Rule
BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No informative BS4-compatible pedigree evidence was retrieved.
Still missing
- No quantitative nonsegregation likelihood ratio or family data were identified.
Sources
BP5 No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified. Review of the BRCA2 clinical-history likelihood-ratio workbook did not find an exact entry for this variant. Details ▾Hide ▴
Rule
BP5 in BRCA2 requires a quantitative multifactorial clinical-history LR of 0.48 or lower.
Evidence considered
- No exact NM_000059.3:c.6859A>T / HGVS_Nucleotide match was identified in the BRCA2 LR workbook.
Still missing
- No exact HGVS match was identified in the reviewed BRCA2 clinical-history LR resource.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks PS2 as not applicable.
Sources
PM1 N/AThis criterion is not applied for BRCA2 in the ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks PM1 as not applicable.
Sources
PM4 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks PM4 as not applicable.
Sources
PM5 N/AThis is a protein-truncating variant in exon 12, and the ENIGMA BRCA2 exon-level table marks exon 12 as PM5_N/A for PTC-based PM5 application. Details ▾Hide ▴
Rule
PM5_PTC is not applicable to BRCA2 exon 12.
Evidence considered
- Exon 12 PTC row shows PM5_N/A in the ENIGMA exon table.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks PM6 as not applicable.
Sources
PP2 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks PP2 as not applicable.
Sources
PP3 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or noncanonical intronic variant targeted by the BRCA2 ENIGMA PP3 bioinformatic rule. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which is below the PP3 splice threshold of 0.20. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 applies to specified missense/in-frame or splice-predicted variant classes.
Evidence considered
- SpliceAI max delta score 0.10.
- BayesDel score 0.566539 was available
- but BRCA2 ENIGMA PP3 is framed for missense/in-frame variants in specified domains or splice-predicted noncanonical variants.
Sources
BP1 N/AThis criterion is intended for silent, missense, or in-frame variants outside clinically important domains without splice impact, and does not apply to this nonsense variant. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP1 applies to silent, missense, or in-frame variants outside key domains with no splice effect.
Evidence considered
- Variant class is nonsense.
- SpliceAI max delta score is 0.10.
Sources
BP2 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks BP2 as not applicable.
Sources
BP3 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks BP3 as not applicable.
Sources
BP4 N/AThis criterion is targeted to missense, in-frame, silent, or intronic variants without predicted splice impact in specific contexts, and does not apply to this nonsense variant. SpliceAI predicts no significant splice effect, with a maximum delta score of 0.10. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 applies to specific nontruncating variant classes with no predicted impact.
Evidence considered
- SpliceAI max delta score 0.10.
- BayesDel score 0.566539 was available
- but BRCA2 ENIGMA BP4 is not designed for nonsense variants.
Sources
BP6 N/AThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in BRCA2 ENIGMA specification.
Evidence considered
- BRCA2 ENIGMA specification marks BP6 as not applicable.
Sources
BP7 N/AThis criterion is designed for silent or certain intronic variants, and does not apply to this nonsense variant. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, but BP7 is not the relevant framework for a protein-truncating change. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 applies to silent or specified intronic variants.
Evidence considered
- Variant class is nonsense.
- SpliceAI max delta score is 0.10.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.3
- Coding (HGVS c.)
- NM_000059.3:c.6859A>T
- Protein (HGVS p.)
- NP_000050.2:p.(Arg2287Ter)
- GRCh38
- chr13:32344575 A>T
- GRCh37
- chr13:32918712 A>T
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.3. Select a row to find it on the plot.
BRCA2NM_000059.3
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 BRCA2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,556,108 alleles
AF 6.43e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.4e-07 · 1 / 1,556,108 alleles · 0 hom
| European (non-Finnish)1 / 1,130,068 | 8.8e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.42629e-07; MAF= 0.00006%, 1/1556108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84903e-07; MAF= 0.00009%, 1/1130068 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AThis variant is a nonsense change rather than a missense, in-frame, silent, or noncanonical intronic variant targeted by the BRCA2 ENIGMA PP3 bioinformatic rule. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which is below the PP3 splice threshold of 0.20. Details ▾Hide ▴
Rule
BRCA2 ENIGMA PP3 applies to specified missense/in-frame or splice-predicted variant classes.
Evidence considered
- SpliceAI max delta score 0.10.
- BayesDel score 0.566539 was available
- but BRCA2 ENIGMA PP3 is framed for missense/in-frame variants in specified domains or splice-predicted noncanonical variants.
Sources
BP4 N/AThis criterion is targeted to missense, in-frame, silent, or intronic variants without predicted splice impact in specific contexts, and does not apply to this nonsense variant. SpliceAI predicts no significant splice effect, with a maximum delta score of 0.10. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP4 applies to specific nontruncating variant classes with no predicted impact.
Evidence considered
- SpliceAI max delta score 0.10.
- BayesDel score 0.566539 was available
- but BRCA2 ENIGMA BP4 is not designed for nonsense variants.
Sources
BP7 N/AThis criterion is designed for silent or certain intronic variants, and does not apply to this nonsense variant. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, but BP7 is not the relevant framework for a protein-truncating change. Details ▾Hide ▴
Rule
BRCA2 ENIGMA BP7 applies to silent or specified intronic variants.
Evidence considered
- Variant class is nonsense.
- SpliceAI max delta score is 0.10.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.566539.
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
1 / 1,556,108 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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1535438831
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/575178/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32918712-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32344575-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.3%3Ac.6859…
- OncoKB ↗www.oncokb.org/gene/BRCA2/R2287*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.6859A%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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= 6.42629e-07; MAF= 0.00006%, 1/1556108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84903e-07; MAF= 0.00009%, 1/1130068 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.566539.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.