About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7976+24G>A, p.?
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.
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
This variant is present in gnomAD v2.1 with a highest non-founder population filter allele frequency of 0.00037674 in East Asian samples, which is above the ENIGMA BRCA2 BS1 strong threshold of 0.0001. This supports BS1 at strong strength.
BP4Supporting
BP4 · supporting
This intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA BRCA2 BP4 threshold of <=0.10. This supports BP4 at supporting strength.
BP7Supporting
BP7 · supporting
This intronic variant is located at +24, which is beyond the conserved donor motif position +7 used in the ENIGMA BRCA2 BP7 rule, and BP4 is met because SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. This supports BP7 at supporting strength.
Recorded classification: Likely benign
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework
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
94 / 1,612,498 alleles
gnomAD v4.1: 94 / 1,612,498 alleles. Recorded AF 5.82946e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78389e-05; MAF= 0.00478%, 12/250842 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000653239; MAF= 0.06532%, 12/18370 alleles, homozygotes = 0); grpmax FAF= 0.00037674.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 3 met · 4 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 NM_000059.4:c.7976+24G>A (NP_000050.3:p.?) variant has been reported in ClinVar (Variation ID 371868), although submission-level classification details were not available in the reviewed record.
This variant is present in population databases, including gnomAD v2.1 at 12/250842 alleles with an East Asian grpmax filter allele frequency of 0.00037674 and gnomAD v4.1 at 94/1612498 alleles; the gnomAD v2.1 frequency exceeds the ENIGMA BRCA2 BS1 strong threshold of 0.0001.
In silico splicing prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.00, consistent with BP4 and BP7 and arguing against PP3.
No criteria match.
Met · 3
BS1 StrongThis variant is present in gnomAD v2.1 with a highest non-founder population filter allele frequency of 0.00037674 in East Asian samples, which is above the ENIGMA BRCA2 BS1 strong threshold of 0.0001. This supports BS1 at strong strength. Details ▾Hide ▴
Rule
BS1_Strong applies when non-founder population FAF is >0.0001 in gnomAD v2.1 and/or v3.1.
Evidence considered
- gnomAD v2.1 East Asian AF 0.000653239 (12/18370).
- gnomAD v2.1 grpmax FAF 0.00037674.
Sources
BP4 SupportingThis intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA BRCA2 BP4 threshold of <=0.10. This supports BP4 at supporting strength. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2, BP4 applies when SpliceAI <=0.10.
Evidence considered
- Variant location c.7976+24.
- SpliceAI max delta score 0.00.
Sources
BP7 SupportingThis intronic variant is located at +24, which is beyond the conserved donor motif position +7 used in the ENIGMA BRCA2 BP7 rule, and BP4 is met because SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. This supports BP7 at supporting strength. Details ▾Hide ▴
Rule
For intronic variants at or beyond +7/-21, BP7 applies if BP4 is met.
Evidence considered
- Variant location c.7976+24.
- SpliceAI max delta score 0.00.
- BP4 criteria are satisfied.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This intronic variant is at c.7976+24, outside the canonical +/-1,2 splice consensus positions and outside the default null-variant categories used for PVS1. No variant-specific RNA study showing a damaging transcript effect was identified, so PVS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 applies to null variants or qualifying RNA evidence; this variant does not meet those entry conditions.
Evidence considered
- BRCA2 has an established loss-of-function disease mechanism in the ENIGMA BRCA2 framework.
- The variant is non-canonical intronic (+24).
- SpliceAI max delta score is 0.00.
Still missing
- Variant-specific RNA assay data could change this assessment if a damaging splicing effect is demonstrated.
Sources
PM2 This variant is present in gnomAD rather than absent from controls. In gnomAD v2.1 it is seen in 12/250842 alleles, so PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting requires absence from gnomAD controls.
Evidence considered
- gnomAD v2.1 total AF 4.78389e-05 with 12 observed alleles.
Sources
PP3 Available computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.00, which is below the ENIGMA BRCA2 PP3 threshold of >=0.20, so PP3 is not met. Details ▾Hide ▴
Rule
For non-canonical intronic variants, ENIGMA BRCA2 PP3 requires SpliceAI >=0.20.
Evidence considered
- SpliceAI max delta score 0.00.
Sources
BA1 The ENIGMA BRCA2 BA1 threshold is a non-founder population filter allele frequency greater than 0.001 in gnomAD v2.1 and/or v3.1. The observed gnomAD v2.1 grpmax FAF is 0.00037674, which is below 0.001, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires non-founder population FAF >0.001 under the ENIGMA BRCA2 specification.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00037674.
- gnomAD v4.1 shows higher frequency but BA1 wording in this VCEP references v2.1 and/or v3.1.
Sources
Not assessed · 10 · no assessment recorded
PS1 No confirmed pathogenic or likely pathogenic comparator with the same demonstrated splicing effect was identified, so PS1 was not assessed. Details ▾Hide ▴
Rule
For intronic variants, ENIGMA BRCA2 PS1 requires the same predicted or confirmed splicing effect as a previously classified pathogenic or likely pathogenic variant.
Evidence considered
- SpliceAI predicts no significant splice impact for this variant.
Still missing
- A validated same-splicing pathogenic comparator would be needed for PS1 evaluation.
Sources
PS3 No calibrated functional assay result for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so PS3 was not assessed. Details ▾Hide ▴
Rule
PS3 requires well-established functional evidence supportive of a damaging effect.
Evidence considered
- No match for c.7976+24G>A was identified in the reviewed ENIGMA Table 9 functional results file.
Still missing
- A variant-specific calibrated functional or RNA study would be needed.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals were identified, so PS4 was not assessed. Details ▾Hide ▴
Rule
PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- No variant-specific PS4 evidence was identified in the reviewed ENIGMA BRCA resources.
Still missing
- A variant-specific case-control analysis meeting ENIGMA thresholds would be needed.
Sources
PM3 No evidence was identified that this variant occurred in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 is reserved for recessive Fanconi anemia presentations with qualifying trans observations.
Evidence considered
- No Fanconi anemia-related co-occurrence data were identified.
Still missing
- Phase and phenotype data would be needed for PM3 evaluation.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation evidence meeting ENIGMA likelihood-ratio thresholds.
Evidence considered
- No family segregation likelihood ratio was available.
Still missing
- Quantitative segregation data would be needed for PP1 evaluation.
Sources
PP4 No variant-specific clinical-history likelihood-ratio entry was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 uses calibrated multifactorial likelihood ratios, with PP4 applying only when LR >=2.08.
Evidence considered
- No exact HGVS nucleotide match for c.7976+24G>A was identified in the BRCA2 clinical-history LR workbook.
Still missing
- Variant-specific multifactorial likelihood data would be needed for PP4 evaluation.
Sources
BS2 No qualifying observations in individuals lacking features of BRCA2-related Fanconi anemia were identified for this variant, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 uses point-based observations in the absence of Fanconi anemia features.
Evidence considered
- No BS2 point-eligible observations were identified.
Still missing
- Point-based recessive phenotype observations would be needed for BS2 evaluation.
Sources
BS3 No calibrated functional assay showing no damaging effect for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so BS3 was not assessed. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence supportive of no damaging effect.
Evidence considered
- No match for c.7976+24G>A was identified in the reviewed ENIGMA Table 9 functional results file.
Still missing
- A variant-specific calibrated functional or RNA study would be needed.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative evidence for lack of segregation meeting ENIGMA likelihood-ratio thresholds.
Evidence considered
- No variant-specific segregation likelihood ratio was identified in the reviewed BRCA resources.
Still missing
- A quantitative segregation likelihood ratio <=0.48 would be needed for BS4 consideration.
Sources
BP5 No variant-specific clinical-history likelihood-ratio entry supporting a benign direction was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 uses calibrated multifactorial likelihood ratios, with BP5 applying only when LR <=0.48.
Evidence considered
- No exact HGVS nucleotide match for c.7976+24G>A was identified in the BRCA2 clinical-history LR workbook.
Still missing
- Variant-specific multifactorial likelihood data would be needed for BP5 evaluation.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists PS2 as not applicable.
Sources
PM1 VCEPThis criterion is not applied independently in the BRCA2 ENIGMA specification and is handled through the bioinformatic framework for other variant classes. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists PM1 as not applicable.
Sources
PM4 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists PM4 as not applicable.
Sources
PM5 N/AIn the BRCA2 ENIGMA framework, PM5 is repurposed for protein-truncating variants in eligible exons. This intronic non-truncating variant does not meet that use case, so PM5 is not applicable. Details ▾Hide ▴
Rule
BRCA2 PM5 is used for PTC logic rather than classic same-residue missense comparison.
Evidence considered
- PM5 candidate review marked this variant ineligible for classic same-residue PM5 and not a PTC-context variant.
Sources
cspec ↗pm5_candidates
PM6 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists PM6 as not applicable.
Sources
PP2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists PP2 as not applicable.
Sources
PP5 VCEPThis criterion is not for use in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification states PP5 is not applicable for this VCEP.
Sources
BP1 N/ABP1 in the BRCA2 ENIGMA specification applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This intronic variant is not in that variant class, so BP1 is not applicable. Details ▾Hide ▴
Rule
BRCA2 BP1 does not apply to intronic variants.
Evidence considered
- Variant class is intronic.
- SpliceAI max delta score 0.00.
Sources
BP2 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists BP2 as not applicable.
Sources
BP3 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists BP3 as not applicable.
Sources
BP6 VCEPThis criterion is not used in the BRCA2 ENIGMA specification. Details ▾Hide ▴
VCEP rule
Not applicable in this VCEP framework.
Evidence considered
- VCEP specification lists BP6 as not applicable.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7976+24G>A
- Protein (HGVS p.)
- NP_000050.3:p.?
- GRCh38
- chr13:32362717 G>A
- GRCh37
- chr13:32936854 G>A
- ClinVar
- 371868
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
94 / 1,612,498 alleles
AF 5.83e-05 · 0 homozygotes · FAF 0.00153
gnomAD v2.1
12 / 250,842 alleles
AF 4.78e-05 · 0 homozygotes · FAF 0.000377
By genetic ancestry
gnomAD v4.1
AF 5.8e-05 · 94 / 1,612,498 alleles · 0 hom · FAF 0.0015
| East Asian83 / 44,860 | 0.0019 |
| South Asian2 / 91,020 | 2.2e-05 |
| European (non-Finnish)9 / 1,178,630 | 7.6e-06 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.8e-05 · 12 / 250,842 alleles · 0 hom · FAF 0.00038
| East Asian12 / 18,370 | 0.00065 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.82946e-05; MAF= 0.00583%, 94/1612498 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0018502; MAF= 0.18502%, 83/44860 alleles, homozygotes = 0); grpmax FAF= 0.00152896.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78389e-05; MAF= 0.00478%, 12/250842 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000653239; MAF= 0.06532%, 12/18370 alleles, homozygotes = 0); grpmax FAF= 0.00037674.
SpliceAI and Pangolin
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 impact with a maximum delta score of 0.00, which is below the ENIGMA BRCA2 BP4 threshold of <=0.10. This supports BP4 at supporting strength. Details ▾Hide ▴
Rule
For intronic variants outside +/-1,2, BP4 applies when SpliceAI <=0.10.
Evidence considered
- Variant location c.7976+24.
- SpliceAI max delta score 0.00.
Sources
BP7 SupportingThis intronic variant is located at +24, which is beyond the conserved donor motif position +7 used in the ENIGMA BRCA2 BP7 rule, and BP4 is met because SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. This supports BP7 at supporting strength. Details ▾Hide ▴
Rule
For intronic variants at or beyond +7/-21, BP7 applies if BP4 is met.
Evidence considered
- Variant location c.7976+24.
- SpliceAI max delta score 0.00.
- BP4 criteria are satisfied.
Sources
PP3 Available computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.00, which is below the ENIGMA BRCA2 PP3 threshold of >=0.20, so PP3 is not met. Details ▾Hide ▴
Rule
For non-canonical intronic variants, ENIGMA BRCA2 PP3 requires SpliceAI >=0.20.
Evidence considered
- SpliceAI max delta score 0.00.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
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PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.American Society of Clinical Oncology · 2003No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.No paper-specific finding is recorded.
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PMID 19305347 ↗ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.No paper-specific finding is recorded.
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
94 / 1,612,498 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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/371868/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32936854-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32362717-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7976…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.7976+24G%3EA
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= 5.82946e-05; MAF= 0.00583%, 94/1612498 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.0018502; MAF= 0.18502%, 83/44860 alleles, homozygotes = 0); grpmax FAF= 0.00152896.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.78389e-05; MAF= 0.00478%, 12/250842 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000653239; MAF= 0.06532%, 12/18370 alleles, homozygotes = 0); grpmax FAF= 0.00037674.
ClinVar
This variant is present in ClinVar (Variation ID: 371868); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).