About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.10027G>T, p.(Glu3343Ter)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (non-cancer, exome) and gnomAD v4.1 (non-cancer) outbred populations. Per ENIGMA PM2 rule, absence from controls in outbred populations qualifies for PM2_Supporting. Read depth at the variant region has not been independently verified but BRCA2 exon 27 is well-covered in exome sequencing.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ENIGMA BRCA1/BRCA2 Table 3 combination rules applied. Only PM2_Supporting is met (absence from gnomAD outbred populations). PVS1 is not applicable per ENIGMA Table 4 (PTC beyond p.E3309 in exon 27). No benign criteria are met. A single pathogenic Supporting criterion does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule in ENIGMA Table 3. Under the ENIGMA point system (1 point from PM2_Supporting, 0 from benign), the total of 1 falls in the Uncertain Significance range (-1 to 5).
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
0.170 maximum delta
Recorded SpliceAI maximum delta score: 0.170. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
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: 1 met · 4 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.10027G>T (p.Glu3343Ter) is a nonsense variant in BRCA2 exon 27 that introduces a premature termination codon at position 3343 of 3418 amino acids.
PVS1 is not applicable per ENIGMA BRCA2 Table 4: nonsense variants in exon 27 beyond codon p.E3309 are assigned PVS1_N/A, as truncation of the extreme C-terminus is not considered sufficient evidence for pathogenicity under the ENIGMA decision framework.
PM2_Supporting is met: the variant is absent from gnomAD v2.1 (non-cancer, exome), gnomAD v4.1 (non-cancer), and gnomAD-Canada v1.0 outbred populations.
PP3 is not met: although BayesDel no-AF score is 0.65 (≥0.30), the variant lies at position 3343, outside the BRCA2 clinically important functional domains (DNA binding domain aa 2481-3186; PALB2 binding domain aa 10-40). SpliceAI max delta is 0.17 (<0.20 threshold).
BA1 and BS1 are not met: the variant is absent from gnomAD; filter allele frequency does not exceed benign population thresholds.
PS3 and BS3 are not assessed: no variant-specific functional assay data were identified in ENIGMA Table 9 or in any of the six reviewed publications.
PP4 and BP5 are not assessed: the variant was not present in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio table; no multifactorial likelihood data are available.
ClinVar reports this variant as Likely benign (1 clinical laboratory, criteria provided, single submitter; variation ID 1770751). PP5 is not applicable under ENIGMA specifications, and no expert panel classification exists to warrant an override.
With only PM2_Supporting met and PVS1 not applicable per ENIGMA Table 4, the available evidence is insufficient to classify this variant as pathogenic or likely pathogenic. Multiple evidence categories (functional, segregation, clinical history, case-control) lack data. The variant remains a variant of uncertain significance (VUS).
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 (non-cancer, exome) and gnomAD v4.1 (non-cancer) outbred populations. Per ENIGMA PM2 rule, absence from controls in outbred populations qualifies for PM2_Supporting. Read depth at the variant region has not been independently verified but BRCA2 exon 27 is well-covered in exome sequencing. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 exomes
- absent from gnomAD v4.1
- absent from gnomAD-Canada v1.0
Still missing
- Read depth at variant position not explicitly verified
- gnomAD coverage assumed adequate for BRCA2 exon 27
Sources
Not met · 4 · evaluated, threshold not reached
PP3 Per ENIGMA PP3 rules: (a) For protein change impact, requires BayesDel no-AF score ≥ 0.30 AND location inside a clinically important functional domain (BRCA2 DNA binding domain aa 2481-3186 or PALB2 binding domain aa 10-40). BayesDel score is 0.65 (≥0.30 threshold met), but the variant is at position 3343, outside both functional domains. (b) For splicing impact, requires SpliceAI ≥ 0.20. SpliceAI max delta score is 0.17, below threshold. Neither PP3 pathway is satisfied. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF: 0.652534 (≥0.30 met but outside functional domain)
- SpliceAI max delta: 0.17 (<0.20 threshold)
Sources
bayesdelspliceai ↗
BA1 Per ENIGMA BA1, filter allele frequency must be above 0.1% (FAF > 0.001) in gnomAD non-founder populations. The variant is absent from gnomAD v2.1 and v4.1; FAF is effectively 0. Details ▾Hide ▴
BS1 Per ENIGMA BS1, BS1_Strong requires FAF > 0.0001 and BS1_Supporting requires FAF > 0.00002 in gnomAD non-founder populations. The variant is absent from gnomAD; neither threshold is met. Details ▾Hide ▴
PS5 PS5 requires a reputable source to have recently reported the variant as pathogenic. The only ClinVar submission for this variant classifies it as Likely benign (1 clinical laboratory, review status: criteria provided, single submitter). No source reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely benign (single submitter
- variation ID 1770751)
Sources
Not assessed · 8 · no assessment recorded
PS3 No variant-specific functional assay data found in ENIGMA Table 9 for c.10027G>T. The variant was not identified in any publication. OncoKB labels it 'Likely Oncogenic' based on inferred loss-of-function from truncation, but this is a computational inference rather than direct experimental evidence and cannot substitute for calibrated functional assay data under ENIGMA PS3 rules. Details ▾Hide ▴
Evidence considered
- OncoKB infers Likely Loss-of-function / Likely Oncogenic by truncation inference
- no direct functional assay data
Still missing
- No calibrated functional assay data for this variant in any published study
Sources
vcep_specifications_table9_v1_2_2024_11_18oncokb ↗
PS4 No case-control data available for this variant. The variant is absent from gnomAD and has not been reported in any case-control study. ENIGMA PS4 requires p≤0.05 and OR≥4 with lower CI excluding 2.0, for which no data exist. Details ▾Hide ▴
Evidence considered
- Variant is absent from population databases
- no case-control enrichment data available
Still missing
- No case-control or cohort enrichment data
Sources
PP1 No co-segregation data available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR ≥ 2.08:1 for Supporting, ≥ 4.3:1 for Moderate, or ≥ 18.7:1 for Strong. Details ▾Hide ▴
Still missing
- No segregation analysis data available
PP4 The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio spreadsheet. No multifactorial likelihood data supporting pathogenicity are available. ENIGMA PP4 requires clinical-history LR ≥ 2.08:1 for Supporting. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table (2182 variants screened)
Still missing
- No clinical-history or multifactorial likelihood data available
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BS2 No data on observation of this variant in healthy adults without features of Fanconi Anemia. ENIGMA BS2 requires proband-level data with point assignment per Specifications Table 8. No such data are available. Details ▾Hide ▴
Still missing
- No proband-level data on observation in healthy adults
BS3 No variant-specific functional assay data showing no damaging effect were found in ENIGMA Table 9 or in any publication. The variant is not listed in the curated functional assay results. Details ▾Hide ▴
Evidence considered
- Variant not found in ENIGMA Table 9 curated functional assay results
Still missing
- No calibrated functional assay data showing no damaging effect
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 No segregation data available for this variant. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤ 0.48:1 for Supporting, ≤ 0.23:1 for Moderate, or ≤ 0.05:1 for Strong. Details ▾Hide ▴
Still missing
- No segregation analysis data available
BP5 The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio spreadsheet. No multifactorial likelihood data supporting benignity are available. ENIGMA BP5 requires clinical-history LR ≤ 0.48:1 for Supporting. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- No clinical-history LR data available
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APer ENIGMA BRCA2 Table 4, nonsense (PTC) variants in exon 27 at codon position > p.E3309 are assigned PVS1_N/A. This variant produces p.Glu3343Ter, which lies beyond the PVS1-applicable C-terminal boundary. Truncation of the extreme C-terminus (last ~75 residues) is not considered sufficient for PVS1 under ENIGMA specifications. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4: BRCA2 exon 27
- PTC>p.E3309 → PVS1_N/A
Sources
vcep_specifications_table4_v1_2_2024_11_18
PS1 N/APS1 applies to predicted missense substitutions or variants with same predicted splicing impact as a classified pathogenic variant. This is a nonsense (PTC) variant, not a missense change, and has no same-residue pathogenic missense comparator. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPPS2 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans; trivially not applicable for this heterozygous BRCA2 variant assessment without Fanconi Anemia phenotype data. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 applies to in-frame deletions/insertions or stop-loss variants; this is a nonsense substitution and PM4 is not applicable per ENIGMA specifications. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APer ENIGMA BRCA2 Table 4, exon 27 PTC variants at codon position > p.E3309 are assigned PM5_N/A. This variant produces p.Glu3343Ter, beyond the PM5_PTC boundary. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4: BRCA2 exon 27
- PTC>p.E3309 → PM5_N/A
Sources
vcep_specifications_table4_v1_2_2024_11_18
PM6 VCEPPM6 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is not applicable under ENIGMA BRCA2 specifications. The ClinVar submission is Likely benign from a single clinical laboratory, not an expert panel classification that would warrant a PP5 override. Details ▾Hide ▴
BP1 N/ABP1 applies to missense, silent, or in-frame variants outside clinically important functional domains with no splicing predicted. This is a nonsense (PTC) variant; BP1 is not designed for nonsense variants under the ENIGMA bioinformatic code flowchart (Figure 1A). Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPBP2 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
BP3 VCEPBP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to this nonsense substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 applies to missense, in-frame, silent, or intronic variants per the ENIGMA bioinformatic code flowchart (Figure 1A). Nonsense (PTC) variants do not enter this flowchart; BP4 is not designed for PTC variants. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not applicable under ENIGMA BRCA2 specifications. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies to silent and intronic variants with no predicted splicing impact, or to variants with well-established mRNA assay data showing no damaging effect. This is a nonsense (PTC) variant; BP7 is not designed for PTC variants. No mRNA assay data are available. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.10027G>T
- Protein (HGVS p.)
- NP_000050.3:p.(Glu3343Ter)
- GRCh38
- chr13:32398540 G>T
- GRCh37
- chr13:32972677 G>T
- ClinVar
- 1770751
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
- 0.653
How the predictions were used
PP3 Per ENIGMA PP3 rules: (a) For protein change impact, requires BayesDel no-AF score ≥ 0.30 AND location inside a clinically important functional domain (BRCA2 DNA binding domain aa 2481-3186 or PALB2 binding domain aa 10-40). BayesDel score is 0.65 (≥0.30 threshold met), but the variant is at position 3343, outside both functional domains. (b) For splicing impact, requires SpliceAI ≥ 0.20. SpliceAI max delta score is 0.17, below threshold. Neither PP3 pathway is satisfied. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF: 0.652534 (≥0.30 met but outside functional domain)
- SpliceAI max delta: 0.17 (<0.20 threshold)
Sources
bayesdelspliceai ↗
BP4 N/ABP4 applies to missense, in-frame, silent, or intronic variants per the ENIGMA bioinformatic code flowchart (Figure 1A). Nonsense (PTC) variants do not enter this flowchart; BP4 is not designed for PTC variants. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to silent and intronic variants with no predicted splicing impact, or to variants with well-established mRNA assay data showing no damaging effect. This is a nonsense (PTC) variant; BP7 is not designed for PTC variants. No mRNA assay data are available. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). BayesDel score = 0.652534.
6 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.Reports that the smallest known cancer-associated BRCA2 deletion removes 224 C-terminal residues and that GFP-tagged BRCA2 deletion mutants reveal two nuclear localization signals within the final 224 residues. Discusses cytoplasmic mislocalization of truncated BRCA2. NM_000059.4:c.10027G>T (p.Glu3343Ter) 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.Examines human and mouse cell lines with different BRCA2 mutations for ability to repair chromosomal breaks by homologous recombination using I-SceI endonuclease. NM_000059.4:c.10027G>T (p.Glu3343Ter) was not identified in the abstract or citation context.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.Reports a new BRCA2 mutation in an Italian healthy woman with familial breast cancer history, discussing heterozygous germline mutations and breast/ovarian cancer susceptibility. NM_000059.4:c.10027G>T (p.Glu3343Ter) was not identified in the abstract or citation context.Does not name this variant
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PMID 22193408 ↗BRCA1 and BRCA2: different roles in a common pathway of genome protection.Review article describing BRCA1 and BRCA2 roles in DNA damage response and homologous recombination. Discusses BRCA2 as a mediator of RAD51 filament formation. NM_000059.4:c.10027G>T (p.Glu3343Ter) 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.Comprehensive review of global BRCA1 and BRCA2 mutation spectrum in breast cancer, cataloguing founder mutations (185delAG, 5382insC, 300T>G) across diverse populations. NM_000059.4:c.10027G>T (p.Glu3343Ter) was not identified in this paper.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. Contains tables of tumor types and referral criteria for hereditary cancer syndromes including HBOC. Does not discuss any specific BRCA2 variants.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 0.170
Open source ↗
ClinVar
1 Likely benign
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/1770751/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32972677-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32398540-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32398540-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.1002…
- OncoKB ↗www.oncokb.org/gene/BRCA2/E3343*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.10027G%3ET
- 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 has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1770751)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). BayesDel score = 0.652534.
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.