About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.7092_7099del, p.(Glu2364AspfsTer25)
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
NM_000059.4:c.7092_7099del is an 8 bp frameshift deletion in BRCA2 exon 14 (c.7008–7435), predicted to produce a premature termination codon at p.(Glu2364AspfsTer25). Loss of function is a well-established disease mechanism for BRCA2. Under ENIGMA BRCA1/2 v1.2.0 Specifications Table 4, protein termination codon (PTC) variants in exon 14 are assigned PVS1 at very strong weight. The truncation occurs upstream of the BRCA2 DNA-binding domain (aa 2481–3186), and the variant is expected to undergo nonsense-mediated decay. No SpliceAI-predicted splicing impact (max delta = 0.01) complicates the null interpretation.
PM2Supporting
PM2 · supporting
Under ENIGMA PM2_Supporting, the variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in all outbred populations. This meets the ENIGMA threshold for PM2 at supporting strength.
PM5Strong
PM5 · strong
ENIGMA Specifications Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA2 exon 14. This exon is not among the PM5_N/A exons (E6, E12, E27). A proven pathogenic PTC variant has been observed in this exon previously, justifying the additional weight beyond PVS1.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1/2 v1.2.0 Table 3: PVS1 (Very Strong) + PM5_PTC (Strong) satisfies the Pathogenic combination rule '1 Very Strong + >=1 Strong'. PM2 (Supporting) provides additional evidence but is not required for this classification.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 3 met · 2 not met · 8 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000059.4:c.7092_7099del (p.Glu2364AspfsTer25) is an 8 bp frameshift deletion in BRCA2 exon 14 that creates a premature termination codon, removing the DNA-binding domain (aa 2481–3186) and nuclear localization signals. It is classified as Pathogenic under ENIGMA BRCA1/2 v1.2.0.
PVS1 (very strong) is applied: ENIGMA Table 4 assigns full PVS1 weight to protein termination codon variants in BRCA2 exon 14. The frameshift is predicted to undergo nonsense-mediated decay and eliminates all C-terminal functional domains.
PM5_PTC (strong) is applied: ENIGMA Table 4 assigns PM5_Strong (PTC) for exon 14 based on the presence of proven pathogenic PTC variants in this exon, providing additional weight beyond PVS1.
PM2 (supporting) is applied: the variant is absent from gnomAD v2.1 (exome, non-cancer), v4.1 (non-cancer), and gnomAD-Canada, meeting the ENIGMA PM2_Supporting threshold.
This combination (PVS1 + PM5_PTC Strong + PM2 Supporting) satisfies the ENIGMA Table 3 rule for Pathogenic: 1 Very Strong + ≥1 Strong criterion.
No criteria match.
Met · 3
PVS1 Very strongNM_000059.4:c.7092_7099del is an 8 bp frameshift deletion in BRCA2 exon 14 (c.7008–7435), predicted to produce a premature termination codon at p.(Glu2364AspfsTer25). Loss of function is a well-established disease mechanism for BRCA2. Under ENIGMA BRCA1/2 v1.2.0 Specifications Table 4, protein termination codon (PTC) variants in exon 14 are assigned PVS1 at very strong weight. The truncation occurs upstream of the BRCA2 DNA-binding domain (aa 2481–3186), and the variant is expected to undergo nonsense-mediated decay. No SpliceAI-predicted splicing impact (max delta = 0.01) complicates the null interpretation. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4: BRCA2 exon 14 PTC variants receive PVS1 at very strong strength
- Frameshift deletion c.7092_7099del in exon 14
- premature stop at p.(Glu2364AspfsTer25)
- The truncation at aa 2364 is upstream of the DNA-binding domain (aa 2481–3186) and the NLS
- eliminating all C-terminal functional regions
- SpliceAI max delta = 0.01 — no confounding cryptic splicing rescue
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM2 SupportingUnder ENIGMA PM2_Supporting, the variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in all outbred populations. This meets the ENIGMA threshold for PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome
- non-cancer)
- Absent from gnomAD v4.1 (non-cancer)
- Absent from gnomAD-Canada v1.0
Sources
PM5 StrongENIGMA Specifications Table 4 assigns PM5_Strong (PTC) for protein termination codon variants in BRCA2 exon 14. This exon is not among the PM5_N/A exons (E6, E12, E27). A proven pathogenic PTC variant has been observed in this exon previously, justifying the additional weight beyond PVS1. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4: BRCA2 exon 14 receives PM5_Strong (PTC)
- Exon 14 is in the PM5_PTC applicable set (not E6
- E12
- or E27)
- Multiple proven pathogenic PTC variants have been observed in exon 14
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
Not met · 2 · evaluated, threshold not reached
BA1 ENIGMA BA1 requires the variant to have a filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only) and/or v3.1 (non-cancer). This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
Sources
BS1 ENIGMA BS1_Strong requires FAF > 0.0001 (0.01%), and BS1_Supporting requires FAF > 0.00002 (0.002%). This variant is absent from all gnomAD populations; neither threshold is met. Details ▾Hide ▴
Not assessed · 8 · no assessment recorded
PS3 No variant-specific functional assay data are available for NM_000059.4:c.7092_7099del. ENIGMA Specifications Table 9 (curated functional assay results) does not include this variant. Table 9 is primarily calibrated for missense and synonymous variants; this frameshift null variant is already captured by PVS1 and PM5_PTC. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9 curated functional assay results
Still missing
- No variant-specific functional assay has been performed
Sources
vcep_specifications_table9_v1_2_2024_11_18
PS4 No case-control study data are available for this variant. The variant is absent from the ENIGMA posterior probability reference set (Supplementary Table 7) and from the Parsons et al. 2019 multifactorial dataset (HUMU-40-1557-s001). No case-control odds ratio or p-value can be computed. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA reference set and Parsons 2019 multifactorial dataset
Still missing
- No case-control or cohort enrichment data for this specific variant
Sources
vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
PP1 No segregation data are available for this variant. ENIGMA PP1 requires a quantitative cosegregation likelihood ratio (LR ≥ 2.08 for supporting, ≥ 4.3 for moderate, ≥ 18.7 for strong). No pedigree or cosegregation analysis has been performed. Details ▾Hide ▴
Still missing
- No family segregation data available
PP4 The variant was not found in Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio table for BRCA2. ENIGMA PP4 requires an LR ≥ 2.08 from multifactorial clinical data. No clinical-history LR is available for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- No clinical-history likelihood ratio data available for this variant
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BS2 ENIGMA BS2 requires a points-based assessment of the absence of Fanconi Anemia features in individuals homozygous or compound heterozygous for the variant. No proband phenotype data are available for this variant. Details ▾Hide ▴
Still missing
- No proband data to assess BS2 points
BS3 ENIGMA BS3 applies to well-established functional studies showing no damaging effect on protein function. This is a frameshift null variant predicted to truncate the protein; BS3 is not biologically plausible for a PTC variant. The variant is not listed in ENIGMA Table 9 curated functional assay results. Details ▾Hide ▴
Evidence considered
- Frameshift PTC variant — BS3 not biologically expected
- Variant absent from ENIGMA Table 9 curated functional assay results
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 ENIGMA BS4 requires a quantitative cosegregation LR ≤ 0.48 showing lack of segregation with disease. No segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
BP5 The variant was not found in Li et al. 2020 (PMID:31853058) clinical-history LR table for BRCA2. ENIGMA BP5 requires an LR ≤ 0.48 from multifactorial clinical data. No clinical-history LR is available for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- No clinical-history likelihood ratio data available for this variant
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AENIGMA PS1 applies to missense substitutions with a previously classified pathogenic comparator, or to exonic/intronic variants with the same predicted splice impact as a known pathogenic variant. NM_000059.4:c.7092_7099del is a frameshift deletion; neither comparator category applies. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PS2 as Not Applicable (de novo criterion not used in this framework). Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PM1 as Not Applicable. Hotspot/domain criteria are not independently used for BRCA2 under this framework. Details ▾Hide ▴
No further detail was recorded.
PM3 N/APM3 was explicitly skipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PM4 as Not Applicable. Protein-length changes are addressed through PVS1 and PM5_PTC instead. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PM6 as Not Applicable (de novo criterion not used in this framework). Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PP2 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AENIGMA PP3 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with BayesDel ≥ 0.30, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). NM_000059.4:c.7092_7099del is a frameshift deletion with SpliceAI max delta = 0.01. Neither criterion is met. Furthermore, ENIGMA guidance specifies not to stack PP3 when PVS1 is already applied for the same evidence stream. Details ▾Hide ▴
Evidence considered
- Frameshift variant — not eligible for PP3 under ENIGMA rules
- SpliceAI max delta = 0.01 — no predicted splicing impact
Sources
PP5 VCEPENIGMA BRCA1/2 v1.2.0 specification lists PP5 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AENIGMA BP1 applies to silent substitutions, missense, or in-frame insertion/deletion variants outside a clinically important functional domain with no splicing predicted. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP1. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPENIGMA BRCA1/2 v1.2.0 specification lists BP2 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPENIGMA BRCA1/2 v1.2.0 specification lists BP3 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AENIGMA BP4 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.18 AND SpliceAI ≤ 0.1), or to silent/intronic variants with no splicing predicted. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP4 under ENIGMA rules. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPENIGMA BRCA1/2 v1.2.0 specification lists BP6 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AENIGMA BP7 applies to silent substitutions or intronic variants with no splicing predicted (meeting BP4), or to mRNA-level functional studies showing no damaging effect. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP7. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not defined in the ENIGMA BRCA1/2 v1.2.0 specification criteria set. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.7092_7099del
- Protein (HGVS p.)
- NP_000050.3:p.(Glu2364AspfsTer25)
- GRCh38
- chr13:32354941 ATGAACATC>A
- GRCh37
- chr13:32929078 ATGAACATC>A
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AENIGMA PP3 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with BayesDel ≥ 0.30, or to variants with predicted splicing impact (SpliceAI ≥ 0.2). NM_000059.4:c.7092_7099del is a frameshift deletion with SpliceAI max delta = 0.01. Neither criterion is met. Furthermore, ENIGMA guidance specifies not to stack PP3 when PVS1 is already applied for the same evidence stream. Details ▾Hide ▴
Evidence considered
- Frameshift variant — not eligible for PP3 under ENIGMA rules
- SpliceAI max delta = 0.01 — no predicted splicing impact
Sources
BP4 N/AENIGMA BP4 applies to missense or in-frame insertion/deletion variants inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.18 AND SpliceAI ≤ 0.1), or to silent/intronic variants with no splicing predicted. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP4 under ENIGMA rules. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AENIGMA BP7 applies to silent substitutions or intronic variants with no splicing predicted (meeting BP4), or to mRNA-level functional studies showing no damaging effect. NM_000059.4:c.7092_7099del is a frameshift deletion; not eligible for BP7. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
5 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
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PMID 10570174 ↗Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.Spain et al. 1999. Demonstrates that C-terminally truncated BRCA2 proteins fail to localize to the nucleus, using GFP-tagged BRCA2 truncation constructs including 6174delT. NM_000059.4:c.7092_7099del was not identified in this paper.Does not name this variant
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PMID 11239455 ↗BRCA2 is required for homology-directed repair of chromosomal breaks.Moynahan et al. 2001. Demonstrates that BRCA2 is required for homology-directed repair of chromosomal double-strand breaks using CAPAN-1 cells (6174delT) and Brca2lex1/lex2 mouse ES cells (exon 27 deletion). NM_000059.4:c.7092_7099del was not identified in this paper.Does not name this variant
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PMID 20878484 ↗A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.Pisano et al. 2011. Reports a novel BRCA2 frameshift mutation c.7525_7526insT (p.Ser2509fs) in exon 15 in an Italian family with breast cancer history. NM_000059.4:c.7092_7099del was not identified in this paper.Does not name this variant
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PMID 22193408 ↗BRCA1 and BRCA2: different roles in a common pathway of genome protection.Roy et al. 2012. Review article comparing BRCA1 and BRCA2 roles in genome protection, focusing on their different stages in the DNA damage response and homologous recombination. NM_000059.4:c.7092_7099del was not identified in this paper.Does not name this variant
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PMID 24312913 ↗A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.Karami and Mehdipour 2013. Comprehensive review of the global spectrum of BRCA1 and BRCA2 mutations in breast cancer. NM_000059.4:c.7092_7099del was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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/?term=NM_000059.4%3Ac.7092_7099del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32929078-ATGAACATC-A?datas…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32354941-ATGAACATC-A?da…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32354941-ATGAACATC-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.7092…
- OncoKB ↗www.oncokb.org/gene/BRCA2/E2364Dfs*25
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.7092_7099del
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.