About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.*23A>C, p.?
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. 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: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
This 3' UTR substitution has no predicted impact on mRNA splicing (SpliceAI max delta = 0.00). The variant is located in exon 27, outside the native donor/acceptor splice sites, and outside the ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186). Per ENIGMA Figure 1A, variants with no predicted splicing impact and no protein-level impact receive BP4 at supporting strength.
Recorded classification: Uncertain significance
Only BP4 (supporting) is met: SpliceAI predicts no splicing impact (max delta = 0.00) and the variant is outside clinically important functional domains. No pathogenic criteria are met. The ENIGMA BRCA2 v1.2 Table 3 likely benign rules require at least 2 Supporting Benign criteria, or 1 Moderate/Strong Benign plus 1 Supporting Benign. A single supporting benign criterion satisfies no combination rule. Under the ENIGMA points-based scoring (conflicting evidence appendix), BP4 supporting contributes -1 point, falling in the VUS 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
3 / 1,611,596 alleles
gnomAD v4.1: 3 / 1,611,596 alleles. Recorded AF 1.86151e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48004e-05; MAF= 0.00648%, 1/15432 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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 ↗
No screenshot for this evidence
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 14 not met · 0 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
NM_000059.4:c.*23A>C is a 3' UTR substitution in BRCA2 exon 27, downstream of the stop codon. SpliceAI predicts no splicing impact (max delta = 0.00) and the variant is outside the clinically important PALB2-binding and DNA-binding domains.
The variant is present at very low frequency in gnomAD (v2.1: 1/31406 genome alleles, 0.00318%; v4.1: 3/1611596 alleles, FAF=2.8e-7) and is absent from gnomAD-Canada. These frequencies are below the ENIGMA BA1 and BS1 thresholds.
This variant has been reported in ClinVar (Variation ID 438948) as Uncertain significance by a single clinical laboratory (1-star review status). Three papers cited in the ClinVar submission (PMID:29208711 on polyadenylation signal recognition, PMID:29648582 on polyadenylation code inference, PMID:26467025 on DNA variant scoring) discuss polyadenylation biology and variant interpretation methodology but do not mention BRCA2 or NM_000059.4:c.*23A>C.
BP4 (supporting) is met: computational evidence (SpliceAI) predicts no splicing impact. No pathogenic, likely pathogenic, or benign criteria beyond BP4 are met given the absence of functional, clinical, segregation, or case-control data specific to this 3' UTR variant.
No criteria match.
Met · 1
BP4 SupportingThis 3' UTR substitution has no predicted impact on mRNA splicing (SpliceAI max delta = 0.00). The variant is located in exon 27, outside the native donor/acceptor splice sites, and outside the ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186). Per ENIGMA Figure 1A, variants with no predicted splicing impact and no protein-level impact receive BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splicing impact
- Variant outside native donor/acceptor splice sites (c.*23
- exon 27 3' UTR)
- Outside ENIGMA clinically important functional domains
Sources
Not met · 14 · evaluated, threshold not reached
PVS1 NM_000059.4:c.*23A>C is a 3' UTR substitution, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 requires a loss-of-function variant type. The generic PVS1 assessment confirms this variant does not fall into any PVS1-eligible bucket. Details ▾Hide ▴
Evidence considered
- Variant is a substitution in the 3' UTR of BRCA2 (exon 27
- downstream of CDS)
- Not a nonsense
- frameshift
- canonical splice site
- initiation codon
- or exon deletion
- ClinGen SVI PVS1 framework does not classify 3' UTR substitutions as null variants
Sources
pvs1_gene_contextpvs1_variant_assessment
PS3 No functional studies test NM_000059.4:c.*23A>C or a systematically characterized range that includes this 3' UTR position. Not listed in ENIGMA Specifications Table 9 for curated functional assay results. The three papers cited in the ClinVar submission (PMID:29208711, 29648582, 26467025) are polyadenylation methodology papers that do not mention BRCA2 or this variant. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: variant not listed
- No variant-specific functional data found in literature
Still missing
- No functional studies available for this 3' UTR variant
Sources
PS4 No case-control data comparing variant prevalence in affected versus unaffected individuals is available for this variant. Details ▾Hide ▴
Still missing
- No case-control study data available
PM2 Variant is present in gnomAD v2.1 (1/31406 genome alleles, AF=3.18e-5) and gnomAD v4.1 (3/1611596 alleles, AF=1.86e-6). ENIGMA PM2_Supporting requires absence from gnomAD v2.1 exome-only subset and v3.1 non-cancer. While absent from the exome-only subset (0/0, region may not be captured by exome), a single observation in an outbred population is explicitly stated as not informative for PM2 per ENIGMA guidance. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/31406 genome alleles (AF=0.00318%)
- exome data unavailable
- gnomAD v4.1: 3/1611596 alleles (AF=0.00019%)
- grpmax FAF=2.8e-7
- ENIGMA guidance: single observation in outbred population not informative for PM2
Sources
PP1 No co-segregation data or likelihood ratio analysis available for this variant. ENIGMA PP1 requires a quantitative co-segregation LR ≥ 2.08. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 SpliceAI predicts no splicing impact (max delta = 0.0). The variant is a 3' UTR substitution, not a missense/in-frame change, so BayesDel is not applicable. ENIGMA PP3 requires either BayesDel no-AF ≥ 0.30 (for missense/in-frame in clinically important domain) or SpliceAI ≥ 0.2 (for predicted splicing impact). Neither condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splicing impact
- BayesDel not applicable (3' UTR variant
- no protein change)
- Not in a clinically important functional domain (PALB2 binding aa 10-40 or DNA binding aa 2481-3186)
Sources
PP4 Variant not found in the ENIGMA clinical history likelihood ratio table (PMID:31853058 BRCA2 clinical_history_LR.xlsx). No LR data available to support PP4. ENIGMA PP4 requires LR ≥ 2.08 from calibrated multifactorial likelihood clinical data. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- No clinical history LR data available for this variant
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BA1 Filtering allele frequency (FAF) of 2.8e-7 in gnomAD v4.1 is well below the ENIGMA BA1 threshold of 0.1% (FAF > 0.001). BA1 stand-alone benign criterion is not triggered. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF = 2.8e-7 (threshold: > 0.001)
- gnomAD v2.1: grpmax FAF not available
Sources
BS1 Filtering allele frequency (FAF) of 2.8e-7 in gnomAD v4.1 is below both the ENIGMA BS1_Strong threshold (FAF > 0.0001) and BS1_Supporting threshold (FAF > 0.00002). The variant is too rare in population databases to satisfy BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF = 2.8e-7
- BS1_Supporting threshold: FAF > 0.00002 — not met
- BS1_Strong threshold: FAF > 0.0001 — not met
Sources
BS2 No co-occurrence data with pathogenic variants in trans is available. ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, assessed via a points system (Specifications Table 8). No proband data available for this variant. Details ▾Hide ▴
Still missing
- No co-occurrence or proband phenotype data available
BS3 Not listed in ENIGMA Specifications Table 9 for curated functional assay results. No published functional studies demonstrate no damaging effect on protein function or splicing for this variant. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: variant not listed
Still missing
- No functional studies showing benign effect available
Sources
vcep_specifications_table9_v1_2_2024_11_18
BS4 No segregation data demonstrating lack of segregation in affected family members is available. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤ 0.48. Details ▾Hide ▴
Still missing
- No segregation data available
BP5 Variant not found in the ENIGMA clinical history likelihood ratio table (PMID:31853058 BRCA2 clinical_history_LR.xlsx). No LR data available to support BP5. ENIGMA BP5 requires LR ≤ 0.48 from calibrated multifactorial likelihood clinical data. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 BRCA2 clinical-history LR table
Still missing
- No clinical history LR data available for this variant
Sources
vcep_pmid_31853058_brca2_clinical_history_lr
BP7 ENIGMA BP7 requires either mRNA assay data demonstrating no damaging effect on splicing (BP7_Strong RNA), or application to silent/intronic variants at specific positions with BP4 already met. This is a 3' UTR substitution — not a silent coding variant and not an intronic variant at the positions specified by ENIGMA. No mRNA splicing assay data is available. Details ▾Hide ▴
Evidence considered
- Not a silent coding variant or intronic variant at specified positions
- No mRNA assay data available
Still missing
- No mRNA transcript/splicing assay data available
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot a missense variant and no predicted splicing impact. No same amino acid change comparator exists for a 3' UTR substitution. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPENIGMA BRCA2 CSPEC declares PS2 Not Applicable. Details ▾Hide ▴
Sources
PM1 VCEPENIGMA BRCA2 CSPEC considers PM1 as a component of bioinformatic analysis (PP3/BP4) and declares it Not Applicable as a standalone criterion. Details ▾Hide ▴
Sources
PM5 N/AENIGMA PM5 is repurposed for protein termination codon (PTC) variants where a different proven pathogenic PTC has been seen in the same exon. This is a 3' UTR substitution, not a PTC variant. PM5 candidates analysis confirms not_applicable. Details ▾Hide ▴
Evidence considered
- Not a PTC or truncating variant
- no same-residue missense comparator applicable
Sources
pm5_candidatescspec ↗
PM6 VCEPENIGMA BRCA2 CSPEC declares PM6 Not Applicable. Details ▾Hide ▴
Sources
PP2 VCEPENIGMA BRCA2 CSPEC declares PP2 Not Applicable. Details ▾Hide ▴
Sources
PP5 VCEPENIGMA BRCA2 CSPEC declares PP5 Not Applicable for this VCEP. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global PP5 override. Details ▾Hide ▴
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a 3' UTR substitution, not a missense variant. The ENIGMA BP1_Strong rule covers silent substitutions, missense, and in-frame variants — 3' UTR substitutions are not enumerated. Details ▾Hide ▴
BP2 VCEPENIGMA BRCA2 CSPEC declares BP2 Not Applicable. Details ▾Hide ▴
Sources
BP6 VCEPENIGMA BRCA2 CSPEC declares BP6 Not Applicable. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global BP6 override. Details ▾Hide ▴
PS5 N/AENIGMA BRCA2 CSPEC declares PS5 Not Applicable for this VCEP. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global PP5 override. Details ▾Hide ▴
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.*23A>C
- Protein (HGVS p.)
- NP_000050.3:p.?
- GRCh38
- chr13:32398793 A>C
- GRCh37
- chr13:32972930 A>C
- ClinVar
- 438948
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
3 / 1,611,596 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
1 / 31,406 alleles
AF 3.18e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,611,596 alleles · 0 hom · FAF 2.8e-07
| Amish1 / 912 | 0.0011 |
| European (non-Finnish)2 / 1,179,164 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,406 alleles · 0 hom
| European (non-Finnish)1 / 15,432 | 6.5e-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= 1.86151e-06; MAF= 0.00019%, 3/1611596 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00109649; MAF= 0.10965%, 1/912 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48004e-05; MAF= 0.00648%, 1/15432 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis 3' UTR substitution has no predicted impact on mRNA splicing (SpliceAI max delta = 0.00). The variant is located in exon 27, outside the native donor/acceptor splice sites, and outside the ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186). Per ENIGMA Figure 1A, variants with no predicted splicing impact and no protein-level impact receive BP4 at supporting strength. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splicing impact
- Variant outside native donor/acceptor splice sites (c.*23
- exon 27 3' UTR)
- Outside ENIGMA clinically important functional domains
Sources
PP3 SpliceAI predicts no splicing impact (max delta = 0.0). The variant is a 3' UTR substitution, not a missense/in-frame change, so BayesDel is not applicable. ENIGMA PP3 requires either BayesDel no-AF ≥ 0.30 (for missense/in-frame in clinically important domain) or SpliceAI ≥ 0.2 (for predicted splicing impact). Neither condition is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splicing impact
- BayesDel not applicable (3' UTR variant
- no protein change)
- Not in a clinically important functional domain (PALB2 binding aa 10-40 or DNA binding aa 2481-3186)
Sources
BP7 ENIGMA BP7 requires either mRNA assay data demonstrating no damaging effect on splicing (BP7_Strong RNA), or application to silent/intronic variants at specific positions with BP4 already met. This is a 3' UTR substitution — not a silent coding variant and not an intronic variant at the positions specified by ENIGMA. No mRNA splicing assay data is available. Details ▾Hide ▴
Evidence considered
- Not a silent coding variant or intronic variant at specified positions
- No mRNA assay data available
Still missing
- No mRNA transcript/splicing assay data available
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
3 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 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016Describes a rules-based DNA variant scoring system for pathogenicity assessment in Mendelian disorders. Applies ACMG/AMP 2015 guidelines to 11,894 variants from 338 genes. NM_000059.4:c.*23A>C was not identified in this paper.Does not name this variant
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PMID 29208711 ↗Molecular basis for the recognition of the human AAUAAA polyadenylation signal.Sun Y et al. · 2018Reports the cryo-EM structure of the human CPSF-160/WDR33/CPSF-30 complex bound to the AAUAAA polyadenylation signal. Elucidates the molecular basis of PAS recognition during pre-mRNA 3'-end processing. NM_000059.4:c.*23A>C was not identified in this paper.Does not name this variant
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PMID 29648582 ↗Inference of the human polyadenylation code.Leung MKK et al. · 2018Develops a deep learning model (polyadenylation code) to predict tissue-specific polyadenylation site strength from genomic sequence. Evaluates the model on ClinVar variants near polyadenylation sites but does not report individual variant-level results for BRCA2 or NM_000059.4:c.*23A>C.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,611,596 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
1 Uncertain significance
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/438948/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32972930-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32398793-A-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/13-32398793-A-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.%2A2…
- OncoKB ↗www.oncokb.org/gene/BRCA2/?
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= 1.86151e-06; MAF= 0.00019%, 3/1611596 alleles, homozygotes = 0) and has highest observed frequency in the Amish population (AF= 0.00109649; MAF= 0.10965%, 1/912 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.1841e-05; MAF= 0.00318%, 1/31406 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48004e-05; MAF= 0.00648%, 1/15432 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 438948)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).