About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.682-30A>C, p.?
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
This variant is too common for a pathogenic BRCA2 variant under the ENIGMA population rule. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BA1 threshold of 0.001, so BA1 is met.
BS1Strong
BS1 · strong
This variant exceeds the ENIGMA BRCA2 BS1 strong threshold for population frequency. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BS1 strong threshold of 0.0001.
BP4Supporting
BP4 · supporting
This intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 BP4 threshold of 0.10. BP4 is met.
BP7Supporting
BP7 · supporting
This intronic variant is located at c.682-30, which is beyond the ENIGMA BRCA2 intronic BP7 boundary of -21, and BP4 is satisfied because SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. BP7 is met.
Recorded classification: Benign
ENIGMA BRCA1/BRCA2 Specification v1.2.0 Table 3 final-classification framework (CSPEC/VCEP override); BA1 alone meets the benign combination rule.
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
391 / 1,349,516 alleles
gnomAD v4.1: 391 / 1,349,516 alleles. Recorded AF 0.000289734. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000536223; MAF= 0.05362%, 136/253626 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0060639; MAF= 0.60639%, 134/22098 alleles, homozygotes = 1); grpmax FAF= 0.00539635.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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: 4 met · 3 not met · 10 not assessed · 11 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.682-30A>C (p.?) variant has been reported in ClinVar as benign by 2 clinical laboratories and likely benign by 2 clinical laboratories.
This variant is present in gnomAD with a group maximum filter allele frequency of 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the ENIGMA BRCA2 BA1 threshold of 0.001 and the BS1 strong threshold of 0.0001.
SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.01, which supports BP4 and BP7 under the ENIGMA BRCA2 splicing rules.
No criteria match.
Met · 4
BA1 Stand aloneThis variant is too common for a pathogenic BRCA2 variant under the ENIGMA population rule. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BA1 threshold of 0.001, so BA1 is met. Details ▾Hide ▴
Rule
BA1 applies when FAF is above 0.1% (0.001) in a non-founder gnomAD population.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00539635.
- gnomAD v4.1 grpmax FAF 0.00494792.
Sources
BS1 StrongThis variant exceeds the ENIGMA BRCA2 BS1 strong threshold for population frequency. The gnomAD group maximum filter allele frequency is 0.00539635 in v2.1 and 0.00494792 in v4.1, both above the BS1 strong threshold of 0.0001. Details ▾Hide ▴
Rule
BS1_Strong applies when FAF is above 0.01% (0.0001) in a non-founder gnomAD population.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00539635.
- gnomAD v4.1 grpmax FAF 0.00494792.
Sources
BP4 SupportingThis intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 BP4 threshold of 0.10. BP4 is met. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2 positions, BP4 applies when SpliceAI <=0.1.
Evidence considered
- Variant position c.682-30 is outside +/-1
- 2 splice sites.
- SpliceAI max delta score 0.01.
Sources
BP7 SupportingThis intronic variant is located at c.682-30, which is beyond the ENIGMA BRCA2 intronic BP7 boundary of -21, and BP4 is satisfied because SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. BP7 is met. Details ▾Hide ▴
Rule
For intronic variants at or beyond +7/-21, BP7 applies if BP4 is met.
Evidence considered
- Variant position c.682-30 is beyond -21.
- SpliceAI max delta score 0.01.
- BP4 criteria are satisfied.
Sources
Not met · 3 · evaluated, threshold not reached
PVS1 This intronic variant is not a canonical +/-1,2 splice-site variant, and no damaging mRNA assay result was identified to support RNA-based PVS1. Available evidence therefore does not support applying PVS1 for BRCA2 c.682-30A>C. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying mRNA-only functional evidence at an appropriate strength.
Evidence considered
- BRCA2 is eligible for PVS1 in the ENIGMA framework.
- The variant is c.682-30A>C
- not a default null-variant class.
- No RNA assay showing a damaging transcript effect was identified.
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 136/253626 alleles (AF 0.000536223) and in gnomAD v4.1 at 391/1349516 alleles (AF 0.000289734), so PM2 is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from controls in an outbred population with adequate coverage.
Evidence considered
- gnomAD v2.1 total AF 0.000536223.
- gnomAD v4.1 total AF 0.000289734.
Sources
PP3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 PP3 threshold of 0.20. PP3 is therefore not met. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2 sites, PP3 requires SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
Not assessed · 10 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic variant with the same established splice effect was identified from the reviewed evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
PS1 in BRCA2 may be used for the same protein effect or the same splicing effect as a classified reference variant.
Evidence considered
- ENIGMA BRCA2 allows PS1 for variants with the same predicted or observed splicing impact as a classified reference variant.
Still missing
- A curated reference-variant match with the same demonstrated splice consequence was not identified.
Sources
PS3 No well-established functional study showing a damaging effect for this specific variant was identified, and no variant-level PS3 assignment was found in the reviewed BRCA2 functional resources. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence or a curated BRCA2 Table 9 assignment.
Evidence considered
- No exact match for c.682-30A>C was found in the reviewed BRCA2 functional assignment table.
Still missing
- No damaging protein assay or calibrated combined assay result was identified for this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 No case-control evidence or quantitative enrichment data meeting the ENIGMA BRCA2 PS4 threshold were identified for this variant, so PS4 was not applied. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals, such as p<=0.05 with OR>=4 and lower CI excluding 2.0.
Evidence considered
- No exact variant-level PS4-supporting entry was identified in the reviewed structured BRCA2 resources.
Still missing
- No odds ratio or case-control dataset showing significant enrichment in affected individuals was identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 was not applied. Details ▾Hide ▴
Rule
PM3 applies only in the BRCA2-related Fanconi anemia setting with qualifying point totals.
Evidence considered
- ENIGMA BRCA2 restricts PM3 to BRCA2-related Fanconi anemia contexts with a point-based system.
Still missing
- No qualifying Fanconi anemia phenotype and phase-confirmed trans observation were identified.
Sources
PP1 No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
PP1 requires a segregation LR of at least 2.08 for Supporting strength, with higher thresholds for stronger weights.
Evidence considered
- ENIGMA BRCA2 requires quantitative segregation analysis for PP1.
Still missing
- No segregation likelihood ratio meeting ENIGMA thresholds was identified.
Sources
PP4 No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 PP4 thresholds was identified for this variant, so PP4 was not applied. Details ▾Hide ▴
Rule
PP4 requires a multifactorial clinical-data LR of at least 2.08, with higher thresholds for stronger weights.
Evidence considered
- No exact c.682-30A>C entry was identified in the BRCA2 clinical-history LR workbook.
Still missing
- No qualifying LR entry for c.682-30A>C was identified in the reviewed BRCA2 clinical-history resource.
Sources
BS2 Although this variant has been observed in population databases, no qualifying BRCA2-related Fanconi anemia point-based evidence was identified to apply BS2 under the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
BS2 in BRCA2 uses a point-based framework tied to absence of Fanconi anemia features rather than simple population presence alone.
Evidence considered
- Population observations alone do not establish ENIGMA BS2 for BRCA2.
Still missing
- No individual-level evidence meeting the BRCA2 BS2 point system was identified.
Sources
BS3 No well-established functional study showing no damaging effect for this specific variant was identified, and no variant-level BS3 assignment was found in the reviewed BRCA2 functional resources. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect or a curated BRCA2 Table 9 assignment.
Evidence considered
- No exact match for c.682-30A>C was found in the reviewed BRCA2 functional assignment table.
Still missing
- No calibrated benign functional assay result or no-aberration mRNA-only assignment was identified for this variant.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
BS4 requires a quantitative lack-of-segregation LR of 0.48 or lower, with stronger thresholds for higher benign weights.
Evidence considered
- No exact variant-level lack-of-segregation evidence was identified in the reviewed structured BRCA2 resources.
Still missing
- No segregation LR at or below ENIGMA benign thresholds was identified.
Sources
BP5 No variant-level multifactorial clinical-history likelihood ratio meeting the ENIGMA BRCA2 BP5 thresholds was identified for this variant, so BP5 was not applied. Details ▾Hide ▴
Rule
BP5 requires a multifactorial clinical-data LR of 0.48 or lower, with lower thresholds for stronger benign weights.
Evidence considered
- No exact c.682-30A>C entry was identified in the BRCA2 clinical-history LR workbook.
Still missing
- No qualifying benign-direction LR entry for c.682-30A>C was identified in the reviewed BRCA2 clinical-history resource.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThe ENIGMA BRCA2 specification does not use PS2 for this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PS2 is listed as not applicable in the BRCA2 VCEP framework.
Sources
PM1 N/APM1 is not used as a standalone criterion in the ENIGMA BRCA2 framework and is instead captured through the bioinformatic workflow when relevant. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PM1 is listed as not applicable in the BRCA2 VCEP framework.
Sources
PM4 N/APM4 is not applicable to this ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PM4 is listed as not applicable in the BRCA2 VCEP framework.
Sources
PM5 N/AIn the ENIGMA BRCA2 framework, PM5 is used for protein termination codon variants in eligible exons. This intronic c.682-30A>C variant is not a protein termination variant, so PM5 does not apply. Details ▾Hide ▴
Rule
PM5 is reserved here for eligible PTC variants with exon-specific applicability.
Evidence considered
- BRCA2 PM5 in this framework is the exon-based PM5_PTC rule.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThe ENIGMA BRCA2 specification does not use PM6 for this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PM6 is listed as not applicable in the BRCA2 VCEP framework.
Sources
PP2 N/AThe ENIGMA BRCA2 specification does not use PP2 for this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PP2 is listed as not applicable in the BRCA2 VCEP framework.
Sources
PP5 N/APP5 is not used in the ENIGMA BRCA2 framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- PP5 is explicitly not applicable in the BRCA2 VCEP framework.
Sources
BP1 N/ABP1 in the ENIGMA BRCA2 framework is used for silent, missense, or in-frame variants with no predicted splice effect. This intronic variant does not fit that rule, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1_Strong in BRCA2 is limited to silent, missense, or in-frame variants outside clinically important domains with no splice effect predicted.
Evidence considered
- BP1 in BRCA2 is not an intronic criterion.
Sources
BP2 N/AThe ENIGMA BRCA2 specification does not use BP2 for this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- BP2 is listed as not applicable in the BRCA2 VCEP framework.
Sources
BP3 N/AThe ENIGMA BRCA2 specification does not use BP3 as a standalone criterion in this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- BP3 is listed as not applicable in the BRCA2 VCEP framework.
Sources
BP6 N/AThe ENIGMA BRCA2 specification does not use BP6 for this framework. Details ▾Hide ▴
Rule
Not applicable in the ENIGMA BRCA2 specification.
Evidence considered
- BP6 is listed as not applicable in the BRCA2 VCEP framework.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.682-30A>C
- Protein (HGVS p.)
- NP_000050.3:p.?
- GRCh38
- chr13:32330889 A>C
- GRCh37
- chr13:32905026 A>C
Gene diagram
Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.
BRCA2NM_000059.4
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 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
391 / 1,349,516 alleles
AF 0.00029 · 1 homozygotes · FAF 0.00495
gnomAD v2.1
136 / 253,626 alleles
AF 0.000536 · 1 homozygotes · FAF 0.0054
By genetic ancestry
gnomAD v4.1
AF 0.00029 · 391 / 1,349,516 alleles · 1 hom · FAF 0.0049
| African/African American375 / 69,458 | 0.00541 hom |
| Remaining individuals10 / 53,468 | 0.00019 |
| Admixed American5 / 57,824 | 8.6e-05 |
| European (non-Finnish)1 / 945,462 | 1.1e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00054 · 136 / 253,626 alleles · 1 hom · FAF 0.0054
| African/African American134 / 22,098 | 0.00611 hom |
| Admixed American2 / 33,220 | 6e-05 |
0 alternate alleles recorded in 6 other groups: 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= 0.000289734; MAF= 0.02897%, 391/1349516 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00539895; MAF= 0.53989%, 375/69458 alleles, homozygotes = 1); grpmax FAF= 0.00494792.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000536223; MAF= 0.05362%, 136/253626 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0060639; MAF= 0.60639%, 134/22098 alleles, homozygotes = 1); grpmax FAF= 0.00539635.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 BP4 threshold of 0.10. BP4 is met. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2 positions, BP4 applies when SpliceAI <=0.1.
Evidence considered
- Variant position c.682-30 is outside +/-1
- 2 splice sites.
- SpliceAI max delta score 0.01.
Sources
BP7 SupportingThis intronic variant is located at c.682-30, which is beyond the ENIGMA BRCA2 intronic BP7 boundary of -21, and BP4 is satisfied because SpliceAI predicts no significant splice effect with a maximum delta score of 0.01. BP7 is met. Details ▾Hide ▴
Rule
For intronic variants at or beyond +7/-21, BP7 applies if BP4 is met.
Evidence considered
- Variant position c.682-30 is beyond -21.
- SpliceAI max delta score 0.01.
- BP4 criteria are satisfied.
Sources
PP3 SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.01, which is below the ENIGMA BRCA2 PP3 threshold of 0.20. PP3 is therefore not met. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2 sites, PP3 requires SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score 0.01.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
391 / 1,349,516 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 ↗
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/225736/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32905026-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32330889-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.682-…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.682-30A%3EC
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= 0.000289734; MAF= 0.02897%, 391/1349516 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00539895; MAF= 0.53989%, 375/69458 alleles, homozygotes = 1); grpmax FAF= 0.00494792.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000536223; MAF= 0.05362%, 136/253626 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.0060639; MAF= 0.60639%, 134/22098 alleles, homozygotes = 1); grpmax FAF= 0.00539635.
ClinVar
This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).