About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7977-1G>C, p.?
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Strong
PVS1 · strong
This canonical splice acceptor variant affects BRCA2 c.7977-1, a site where loss of function is an established disease mechanism. ENIGMA Table 4 specifically assigns c.7977-1G>C as PVS1_Strong (RNA) because variants at this splice site are reported to cause leaky abnormal splicing, so full-strength PVS1 is reduced to Strong.
PP4Moderate
PP4 · moderate
A BRCA2 clinical-history likelihood-ratio analysis reported this variant in 7 probands with LR 7.22, which is above the ENIGMA PP4 Moderate threshold of 4.3 and below the Strong threshold of 18.7.
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
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules from the official CSPEC/VCEP 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
5 / 1,612,350 alleles
gnomAD v4.1: 5 / 1,612,350 alleles. Recorded AF 3.10106e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
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.
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: 3 met · 9 not met · 7 not assessed · 9 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.7977-1G>C (p.?) variant has been reported in ClinVar as pathogenic, including review by the ClinGen ENIGMA BRCA1/2 expert panel.
This variant is present at very low frequency in population databases, with 2/281032 alleles in gnomAD v2.1 (AF 7.12e-06) and 5/1612350 alleles in gnomAD v4.1 (AF 3.10e-06; grpmax FAF 1.24e-06), which is too low for BS1 or BA1 but means PM2 is not met because the variant is not absent from controls.
A BRCA2 clinical-history likelihood-ratio analysis reported LR 7.22 across 7 probands, which meets ENIGMA PP4_Moderate.
RNA evidence cited by ENIGMA indicates that variants at this splice acceptor site cause leaky abnormal splicing, and ENIGMA specifically assigns c.7977-1G>C as PVS1_Strong (RNA).
SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, which supports splice disruption but is not separately counted as PP3 because the variant is at a canonical splice position already captured by PVS1.
No criteria match.
Met · 3
PVS1 StrongThis canonical splice acceptor variant affects BRCA2 c.7977-1, a site where loss of function is an established disease mechanism. ENIGMA Table 4 specifically assigns c.7977-1G>C as PVS1_Strong (RNA) because variants at this splice site are reported to cause leaky abnormal splicing, so full-strength PVS1 is reduced to Strong. Details ▾Hide ▴
Rule
ENIGMA Table 4 variant-specific splice-site assignment for BRCA2 exon 18.
Evidence considered
- Canonical splice acceptor variant at c.7977-1
- BRCA2 loss of function established as disease mechanism
- ENIGMA Table 4 row for c.7977-1G>C assigns PVS1_Strong (RNA)
- Splicing data report exon 18 deletion and related abnormal transcripts
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:16211554 ↗
PP4 ModerateA BRCA2 clinical-history likelihood-ratio analysis reported this variant in 7 probands with LR 7.22, which is above the ENIGMA PP4 Moderate threshold of 4.3 and below the Strong threshold of 18.7. Details ▾Hide ▴
Rule
ENIGMA PP4 uses multifactorial clinical likelihood ratios only.
Evidence considered
- Li et al. BRCA2 clinical-history LR 7.223215162037175
- 7 probands
- ENIGMA PP4 Moderate threshold LR >=4.3
Sources
Not met · 9 · evaluated, threshold not reached
PS3 Available functional evidence is based on RNA splicing studies rather than protein-function assays, and ENIGMA directs damaging mRNA-only evidence to PVS1(RNA) instead of PS3. Details ▾Hide ▴
Rule
ENIGMA PS3 is for damaging protein-function studies or combined mRNA/protein studies; mRNA-only damaging evidence is handled under PVS1(RNA).
Evidence considered
- Splicing assay evidence with abnormal transcripts
- No ENIGMA Table 9 PS3 assignment identified for this variant
Still missing
- Calibrated protein-function or combined mRNA/protein evidence meeting ENIGMA PS3 rules
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 2/281032 alleles (AF 7.12e-06) and in gnomAD v4.1 at 5/1612350 alleles (AF 3.10e-06), so ENIGMA PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA PM2 Supporting requires absence from controls.
Evidence considered
- gnomAD v2.1 total AF 7.11663e-06
- 2/281032 alleles
- gnomAD v4.1 total AF 3.10106e-06
- 5/1612350 alleles
Sources
BA1 Population frequency is far below the ENIGMA BA1 threshold. In gnomAD v4.1 the grpmax FAF is 1.24e-06, which is below the BA1 threshold of 0.001. Details ▾Hide ▴
Rule
ENIGMA BA1 uses founder-excluded FAF >0.001.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06
- ENIGMA BA1 threshold FAF >0.001
Sources
BS1 Population frequency does not meet ENIGMA BS1 thresholds. In gnomAD v4.1 the grpmax FAF is 1.24e-06, which is below the Supporting threshold of 2.0e-05 and below the Strong threshold of 1.0e-04. Details ▾Hide ▴
Rule
ENIGMA BS1 uses founder-excluded FAF thresholds.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06
- ENIGMA BS1 Supporting threshold FAF >2.0e-05
- ENIGMA BS1 Strong threshold FAF >1.0e-04
Sources
BS3 Available functional evidence does not support BS3. Reported RNA studies indicate abnormal splicing, and ENIGMA routes damaging mRNA-only evidence to PVS1(RNA) rather than BS3. Details ▾Hide ▴
Rule
ENIGMA BS3 requires well-established studies showing no damaging effect.
Evidence considered
- Splicing studies showed abnormal transcripts
- No benign protein-function study assignment identified in ENIGMA Table 9
Sources
BP1 BP1 is not met because this is a canonical splice-site variant with predicted splice disruption, not a silent, missense, or in-frame variant outside a critical domain with no predicted splice impact. Details ▾Hide ▴
Rule
ENIGMA BP1_Strong applies to silent, missense, or in-frame variants without predicted splice impact.
Evidence considered
- Canonical -1 splice acceptor variant
- SpliceAI max delta score 0.95
Sources
BP4 This canonical splice acceptor variant is not eligible for BP4 because SpliceAI predicts splice disruption with a max delta score of 0.95, which is above the ENIGMA no-impact threshold of 0.1. Details ▾Hide ▴
Rule
ENIGMA BP4 Supporting requires no predicted splice impact for intronic variants outside +/-1,2 or silent variants.
Evidence considered
- SpliceAI max delta score 0.95
- ENIGMA BP4 requires no predicted splice impact with SpliceAI 0.1 or lower
Sources
BP5 The BRCA2 clinical-history likelihood ratio is 7.22, which is above 2.08 and therefore supports pathogenicity rather than benignity. This is above the ENIGMA BP5 benign thresholds of 0.48, 0.23, and 0.05. Details ▾Hide ▴
Rule
ENIGMA BP5 uses multifactorial clinical likelihood ratios only.
Evidence considered
- Clinical-history LR 7.223215162037175
- ENIGMA BP5 Supporting threshold LR <=0.48
Sources
BP7 BP7 is not met because this variant is at a canonical -1 splice position and available RNA data support abnormal splicing rather than no impact on the transcript. Details ▾Hide ▴
Rule
ENIGMA BP7 applies to noncanonical intronic or silent variants with no splice impact or benign RNA-only evidence.
Evidence considered
- Canonical -1 splice acceptor variant
- SpliceAI max delta score 0.95
- Reported abnormal splicing in RNA studies
Sources
Not assessed · 7 · no assessment recorded
PS1 No criterion-ready ENIGMA PS1 comparison variant with the same established splice effect was identified from the reviewed materials, so PS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA PS1 for splicing depends on a previously classified variant with the same splice impact.
Evidence considered
- No reviewed PS1 comparison entry identified
Still missing
- Authoritative ENIGMA Table 5 style reference variant with the same splice consequence and known classification
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been observed in affected individuals, but no case-control analysis with p-value 0.05 or lower and odds ratio 4 or higher was identified, so PS4 cannot be assigned from the reviewed evidence. Details ▾Hide ▴
Rule
ENIGMA PS4 requires a qualifying case-control study result.
Evidence considered
- ClinVar pathogenic observations
- HUMU multifactorial data available but no qualifying PS4 case-control statistic identified
Still missing
- Qualifying ENIGMA case-control statistics for PS4
Sources
PM3 No evidence was identified for biallelic occurrence with a BRCA2-related Fanconi anemia phenotype, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
ENIGMA PM3 is limited to BRCA1/2-related Fanconi anemia contexts.
Evidence considered
- No PM3-specific proband or phase data identified
Still missing
- Documented phase and phenotype data for recessive BRCA2-related Fanconi anemia
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 BRCA2 exon 18 is a PM5_PTC-applicable exon in ENIGMA Table 4, but a clear criterion-ready PM5 assignment was not identified for this leaky splice variant independent of the PVS1(RNA) assessment, so PM5 was not applied in this pass. Details ▾Hide ▴
Rule
ENIGMA PM5 for PTC variants depends on exon-level Table 4 applicability and variant interpretation context.
Evidence considered
- Exon 18 listed as PM5_Strong (PTC)-applicable in Table 4
- Variant-specific row focuses on PVS1_Strong (RNA) because of leaky splicing
Still missing
- Direct ENIGMA confirmation that PM5_PTC should be awarded for this specific c.7977-1G>C splice variant
Sources
vcep_specifications_table4_v1_2_2024_11_18cspec ↗
PP1 No quantitative co-segregation data were identified, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
ENIGMA PP1 requires quantitative co-segregation likelihood ratios.
Evidence considered
- No segregation dataset identified for this variant
Still missing
- Quantitative segregation likelihood ratio from informative families
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS2 No BRCA2-specific BS2 point-based evidence was identified, and this variant was not observed as a homozygote in gnomAD, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
ENIGMA BS2 requires point-based evidence in individuals without Fanconi anemia features.
Evidence considered
- 0 homozygotes in gnomAD v2.1
- 0 homozygotes in gnomAD v4.1
- No BS2 point-based evidence identified
Still missing
- Documented adult observations without Fanconi anemia features under ENIGMA Table 8
Sources
BS4 No quantitative lack-of-segregation data were identified, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
ENIGMA BS4 requires a quantitative non-segregation likelihood ratio.
Evidence considered
- No BS4 segregation likelihood ratio identified
Still missing
- Quantitative non-segregation likelihood ratio from informative families
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM1 N/APM1 is not applicable in the ENIGMA BRCA2 specification for this type of splice-site variant. Details ▾Hide ▴
PM4 N/APM4 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PM6 N/APM6 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
PP3 N/APP3 is not applied for this canonical +/-1 splice variant. ENIGMA PP3 for intronic variants is directed to sites outside the donor and acceptor 1,2 positions, and the generic PVS1 framework also advises against stacking PP3 on the same splice prediction evidence. Details ▾Hide ▴
Rule
ENIGMA PP3 does not separately score canonical +/-1,2 splice-site prediction already captured by PVS1.
Evidence considered
- Variant is at c.7977-1
- SpliceAI max delta score 0.95
- PVS1 scaffold warns not to stack PP3 for the same splice evidence
Sources
BP2 N/ABP2 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the ENIGMA BRCA2 specification. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7977-1G>C
- Protein (HGVS p.)
- NP_000050.3:p.?
- GRCh38
- chr13:32363178 G>C
- GRCh37
- chr13:32937315 G>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
5 / 1,612,350 alleles
AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
2 / 281,032 alleles
AF 7.12e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,612,350 alleles · 0 hom · FAF 1.2e-06
| European (non-Finnish)5 / 1,179,106 | 4.2e-06 |
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.
gnomAD v2.1
AF 7.1e-06 · 2 / 281,032 alleles · 0 hom
| European (non-Finnish)2 / 128,186 | 1.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 This canonical splice acceptor variant is not eligible for BP4 because SpliceAI predicts splice disruption with a max delta score of 0.95, which is above the ENIGMA no-impact threshold of 0.1. Details ▾Hide ▴
Rule
ENIGMA BP4 Supporting requires no predicted splice impact for intronic variants outside +/-1,2 or silent variants.
Evidence considered
- SpliceAI max delta score 0.95
- ENIGMA BP4 requires no predicted splice impact with SpliceAI 0.1 or lower
Sources
BP7 BP7 is not met because this variant is at a canonical -1 splice position and available RNA data support abnormal splicing rather than no impact on the transcript. Details ▾Hide ▴
Rule
ENIGMA BP7 applies to noncanonical intronic or silent variants with no splice impact or benign RNA-only evidence.
Evidence considered
- Canonical -1 splice acceptor variant
- SpliceAI max delta score 0.95
- Reported abnormal splicing in RNA studies
Sources
PP3 N/APP3 is not applied for this canonical +/-1 splice variant. ENIGMA PP3 for intronic variants is directed to sites outside the donor and acceptor 1,2 positions, and the generic PVS1 framework also advises against stacking PP3 on the same splice prediction evidence. Details ▾Hide ▴
Rule
ENIGMA PP3 does not separately score canonical +/-1,2 splice-site prediction already captured by PVS1.
Evidence considered
- Variant is at c.7977-1
- SpliceAI max delta score 0.95
- PVS1 scaffold warns not to stack PP3 for the same splice evidence
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).
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
5 / 1,612,350 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/38132/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32937315-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32363178-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7977…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=123595977
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= 3.10106e-06; MAF= 0.00031%, 5/1612350 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.2405e-06; MAF= 0.00042%, 5/1179106 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.11663e-06; MAF= 0.00071%, 2/281032 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56023e-05; MAF= 0.00156%, 2/128186 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.95).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV104701362, n = 1 times).