About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7673_7674del, p.(Glu2558ValfsTer7)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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
PVS1Very strong
PVS1 · very strong
This variant is a frameshift deletion predicted to produce p.(Glu2558ValfsTer7). Under the ENIGMA BRCA2 specification, loss of function is an established disease mechanism for BRCA2, and exon 16 is annotated as eligible for PVS1; therefore this truncating variant meets PVS1 at Very Strong strength.
PM5Strong
PM5 · strong
This variant creates a premature termination codon in BRCA2 exon 16. In the ENIGMA BRCA2 exon-level truncating-variant table, exon 16 is annotated for PM5_PTC at Strong strength, indicating that a different proven pathogenic truncating variant has been established in this exon and supporting additional pathogenic weight.
PP5Supporting
PP5 · supporting
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 adapted ACMG/AMP criteria-combination rules)
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 / 1,613,678 alleles
gnomAD v4.1: 1 / 1,613,678 alleles. Recorded AF 6.19702e-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: 3 met · 5 not met · 7 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.7673_7674delAG (p.Glu2558ValfsTer7; p.E2558Vfs*7) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including ENIGMA expert panel review.
This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1,613,678 alleles; total AF 6.197e-07; highest observed population AF 1.098e-05 in South Asian individuals), supporting extremely low population frequency but not complete absence from population databases.
Under the ENIGMA BRCA2 loss-of-function framework, this exon 16 frameshift is eligible for PVS1, and the exon-level truncating-variant table assigns additional PM5_PTC evidence at Strong strength for this exon.
SpliceAI predicts possible splice impact with a maximum delta score of 0.24, while REVEL and BayesDel are not applicable to this deletion; this computational result was reviewed but not used as separate PP3 evidence because the variant was adjudicated through the loss-of-function framework.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a frameshift deletion predicted to produce p.(Glu2558ValfsTer7). Under the ENIGMA BRCA2 specification, loss of function is an established disease mechanism for BRCA2, and exon 16 is annotated as eligible for PVS1; therefore this truncating variant meets PVS1 at Very Strong strength. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 for truncating variants in eligible exons
Evidence considered
- Frameshift consequence p.(Glu2558ValfsTer7)
- BRCA2 loss of function established in the official ENIGMA framework
- ENIGMA Table 4 marks exon 16 as PVS1
Sources
PM5 StrongThis variant creates a premature termination codon in BRCA2 exon 16. In the ENIGMA BRCA2 exon-level truncating-variant table, exon 16 is annotated for PM5_PTC at Strong strength, indicating that a different proven pathogenic truncating variant has been established in this exon and supporting additional pathogenic weight. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5_PTC exon-level rule
Evidence considered
- Frameshift with premature termination codon
- ENIGMA Table 4 exon 16 annotation: PM5_Strong (PTC)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
Not met · 5 · evaluated, threshold not reached
PM2 This variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 (1/1,613,678 alleles; total AF 6.197e-07; highest observed population AF 1.098e-05 in South Asian individuals). Because the ENIGMA PM2 rule requires absence from control datasets, PM2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2 requires absence from controls
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 AC 1/AN 1613678
- Highest subpopulation AF 1.098e-05
Sources
PP4 In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband. This is below the ENIGMA PP4 Supporting threshold of 2.08, so PP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 clinical-history LR thresholds
Evidence considered
- Clinical-history LR 1.833293743162062
- N probands 1
- PP4 Supporting threshold 2.08
Sources
BA1 This variant does not meet the ENIGMA BA1 threshold. It is absent from gnomAD v2.1 and is present once in gnomAD v4.1 with total AF 6.197e-07, far below the BA1 stand-alone threshold of 0.001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 frequency threshold
Evidence considered
- gnomAD v4.1 total AF 6.197e-07
- BA1 threshold 0.001
Sources
BS1 This variant does not meet the ENIGMA BS1 threshold. It is absent from gnomAD v2.1 and present once in gnomAD v4.1 with total AF 6.197e-07 and highest observed population AF 1.098e-05, which are below the BS1 Supporting threshold of 0.00002 and the Strong threshold of 0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 frequency thresholds
Evidence considered
- gnomAD v4.1 total AF 6.197e-07
- Highest population AF 1.098e-05
- BS1 thresholds 0.00002 and 0.0001
Sources
BP5 In the BRCA2 clinical-history likelihood-ratio dataset, this variant has LR 1.833 in 1 proband. This is above the BP5 Supporting threshold of 0.48, so BP5 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 clinical-history LR thresholds
Evidence considered
- Clinical-history LR 1.833293743162062
- N probands 1
- BP5 Supporting threshold 0.48
Sources
Not assessed · 7 · no assessment recorded
PS3 No variant-specific calibrated functional assay result for this deletion was identified in the ENIGMA BRCA2 functional assay table, so PS3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 Table 9 functional evidence requirement
Evidence considered
- No Table 9 entry for c.7673_7674del / p.(Glu2558ValfsTer7)
Still missing
- No variant-specific calibrated protein or combined mRNA/protein assay result was identified
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 This variant has been reported in ClinVar, but no case-control dataset or other quantified enrichment evidence meeting the ENIGMA PS4 requirement was identified. Available observations are insufficient to show a statistically increased prevalence in affected individuals compared with controls. Details ▾Hide ▴
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, so PM3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 requires Fanconi anemia-specific data
Still missing
- No Fanconi anemia phenotype or qualifying in-trans observation identified
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 requires quantitative co-segregation evidence
Still missing
- No quantitative co-segregation likelihood ratio identified
Sources
BS2 No qualifying data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 scoring framework, so BS2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 requires phenotype-based point assignment
Still missing
- No BS2 point-based phenotype data identified
Sources
BS3 No variant-specific calibrated functional study showing no damaging effect was identified for this deletion, so BS3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 Table 9 functional evidence requirement
Evidence considered
- No Table 9 entry for c.7673_7674del / p.(Glu2558ValfsTer7)
Still missing
- No benign functional assay result identified in the ENIGMA functional table
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 requires quantitative non-segregation evidence
Still missing
- No quantitative non-segregation likelihood ratio identified
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is intended for variants with the same amino acid change as a previously classified pathogenic variant, or the same predicted splicing effect as a known pathogenic splice variant. This frameshift deletion was not evaluated under a same-amino-acid-change or same-splice-outcome PS1 scenario. Details ▾Hide ▴
PS2 N/ANo de novo framework was applicable for this review. Details ▾Hide ▴
PM1 N/APM1 is not used for this BRCA2 review framework. Details ▾Hide ▴
PM4 N/APM4 is not used for this BRCA2 review framework. Details ▾Hide ▴
PM6 N/ANo assumed de novo framework was applicable for this review. Details ▾Hide ▴
PP2 N/APP2 is not used for this BRCA2 review framework. Details ▾Hide ▴
PP3 N/ASpliceAI predicts possible splice impact with a maximum delta score of 0.24, but PP3 was not applied because this is a frameshift deletion already evaluated under the loss-of-function framework. REVEL and BayesDel were not available for this deletion, and the ENIGMA PP3 rule is not the primary route for this variant type. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 computational rule
Evidence considered
- SpliceAI max delta score 0.24
- REVEL not applicable to this deletion
- BayesDel not applicable to this deletion
Sources
BP1 N/ABP1 is intended for silent, missense, or in-frame variants outside clinically important domains without predicted splice impact, and does not apply to this frameshift deletion. Details ▾Hide ▴
BP2 N/ABP2 is not used for this BRCA2 review framework. Details ▾Hide ▴
BP3 N/ABP3 is not used for this BRCA2 review framework. Details ▾Hide ▴
BP4 N/ABP4 is intended for missense, in-frame, silent, or certain intronic variants without predicted impact. This frameshift deletion is not an eligible BP4 variant type. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 computational rule
Evidence considered
- Variant type is frameshift
- SpliceAI reviewed but BP4 route is not applicable
Sources
BP6 N/ABP6 is not used for this BRCA2 review framework. Details ▾Hide ▴
BP7 N/ABP7 is intended for silent or certain intronic variants with no evidence of splice disruption, and does not apply to this frameshift deletion. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 specification
Evidence considered
- Variant type is frameshift
- SpliceAI reviewed but BP7 route is not applicable
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7673_7674del
- Protein (HGVS p.)
- NP_000050.3:p.(Glu2558ValfsTer7)
- GRCh38
- chr13:32357794 CAG>C
- GRCh37
- chr13:32931931 CAG>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
1 / 1,613,678 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,678 alleles · 0 hom
| South Asian1 / 91,058 | 1.1e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19702e-07; MAF= 0.00006%, 1/1613678 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.0982e-05; MAF= 0.00110%, 1/91058 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/ASpliceAI predicts possible splice impact with a maximum delta score of 0.24, but PP3 was not applied because this is a frameshift deletion already evaluated under the loss-of-function framework. REVEL and BayesDel were not available for this deletion, and the ENIGMA PP3 rule is not the primary route for this variant type. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 computational rule
Evidence considered
- SpliceAI max delta score 0.24
- REVEL not applicable to this deletion
- BayesDel not applicable to this deletion
Sources
BP4 N/ABP4 is intended for missense, in-frame, silent, or certain intronic variants without predicted impact. This frameshift deletion is not an eligible BP4 variant type. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 computational rule
Evidence considered
- Variant type is frameshift
- SpliceAI reviewed but BP4 route is not applicable
Sources
BP7 N/ABP7 is intended for silent or certain intronic variants with no evidence of splice disruption, and does not apply to this frameshift deletion. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 specification
Evidence considered
- Variant type is frameshift
- SpliceAI reviewed but BP7 route is not applicable
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).
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 / 1,613,678 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/38113/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32931931-CAG-C?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32357794-CAG-C?dataset=…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7673…
- OncoKB ↗www.oncokb.org/gene/BRCA2/E2558Vfs*7
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.7673_7674del
- 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= 6.19702e-07; MAF= 0.00006%, 1/1613678 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.0982e-05; MAF= 0.00110%, 1/91058 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (13 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).
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.