About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.2259T>C, p.(Phe753=)
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP1Strong
BP1 · strong
This is a synonymous BRCA2 variant outside the ENIGMA-defined clinically important domains, and SpliceAI predicts no splice effect (max delta score 0.00, below the <=0.1 threshold), which meets BP1_Strong.
Recorded classification: Uncertain significance
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules via final_classification_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
3 / 1,614,118 alleles
gnomAD v4.1: 3 / 1,614,118 alleles. Recorded AF 1.8586e-06. 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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 1 met · 6 not met · 11 not assessed · 10 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.2259T>C (p.Phe753=) variant has been reported in ClinVar with only likely benign submissions.
This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 3/1614118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), which is far below ENIGMA BRCA2 BA1 and BS1 thresholds but does not satisfy absence from controls for PM2.
SpliceAI predicts no meaningful splice effect for this synonymous change (max delta score 0.00), and codon 753 lies outside the ENIGMA-defined BRCA2 clinically important domains, supporting BP1_Strong and not supporting PP3 or PVS1.
No criteria match.
Met · 1
BP1 StrongThis is a synonymous BRCA2 variant outside the ENIGMA-defined clinically important domains, and SpliceAI predicts no splice effect (max delta score 0.00, below the <=0.1 threshold), which meets BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP1_Strong for silent variants outside clinically important domains with SpliceAI <=0.1
Evidence considered
- Protein consequence is p.(Phe753=).
- ENIGMA clinically important BRCA2 domains are aa 10-40 and aa 2481-3186
- codon 753 is outside these regions.
- SpliceAI max delta score is 0.00.
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This synonymous variant does not fall within the BRCA2 null-variant or canonical splice-site categories used for PVS1, and SpliceAI predicts no splice disruption (max delta score 0.00), so available evidence does not support a loss-of-function effect for this criterion. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PVS1 / generic PVS1 scaffold for non-null variants
Evidence considered
- BRCA2 is PVS1-eligible at the gene level under the ENIGMA specification.
- c.2259T>C is a synonymous change outside the default generic PVS1 null-variant buckets.
- SpliceAI max delta score is 0.00.
Still missing
- RNA study or transcript assay data showing an abnormal splice effect would be needed to reconsider PVS1 for a synonymous change.
Sources
PM2 This variant is not absent from controls because it is present in gnomAD v4.1 at 3/1,614,118 alleles (AF 1.8586e-06; grpmax FAF 6.8e-07), so available population data do not support PM2. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM2_Supporting absence from controls rule
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 at AF 1.8586e-06 with grpmax FAF 6.8e-07.
Still missing
- If a BRCA2 VCEP-specified non-cancer population dataset with complete absence were available
- PM2 could be revisited.
Sources
PP3 SpliceAI predicts no meaningful splice effect for this synonymous variant (max delta score 0.00), which is below the ENIGMA BRCA2 PP3 splice threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 splice threshold SpliceAI >=0.2
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.0
- max delta 0.00.
Still missing
- Variant-specific RNA data would be needed if a splice effect remained clinically suspected despite the negative prediction.
Sources
BA1 The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is well below the ENIGMA BRCA2 BA1 threshold of greater than 0.001, so BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BA1 frequency threshold FAF >0.001
Evidence considered
- gnomAD v4.1 grpmax FAF 6.8e-07.
Sources
BS1 The observed gnomAD v4.1 grpmax FAF is 6.8e-07, which is below both the ENIGMA BRCA2 BS1 Supporting threshold of greater than 0.00002 and the Strong threshold of greater than 0.0001, so BS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS1 frequency thresholds
Evidence considered
- gnomAD v4.1 grpmax FAF 6.8e-07.
Sources
BP4 SpliceAI predicts no splice effect (max delta score 0.00), but the ENIGMA BRCA2 BP4 rule for silent variants is limited to synonymous variants inside clinically important domains; this variant is at codon 753, outside those domains, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 silent-variant domain rule
Evidence considered
- SpliceAI max delta score is 0.00.
- Codon 753 is outside the ENIGMA BRCA2 clinically important domains aa 10-40 and aa 2481-3186.
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified that this variant produces the same proven pathogenic protein or splice consequence as a previously classified pathogenic or likely pathogenic BRCA2 variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS1 same protein / same splice consequence rule
Evidence considered
- ENIGMA BRCA2 PS1 depends on a same protein or same splice consequence comparator.
- No such comparator was identified in the reviewed materials.
Still missing
- A validated same-consequence pathogenic or likely pathogenic comparator would be needed for PS1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS3 No calibrated BRCA2 functional assay result for this exact variant was identified in the reviewed BRCA2 functional datasets, so PS3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS3 calibrated functional evidence rule
Evidence considered
- No exact c.2259T>C or p.(F753=) match was identified in the BRCA2 VCEP functional table.
- No exact match was identified in the reviewed multifactorial/functional supporting workbook.
Still missing
- A variant-specific calibrated functional or RNA assay showing a damaging effect would be needed for PS3.
Sources
PS4 No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals was identified, so PS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PS4 case-control enrichment rule
Evidence considered
- ClinVar shows likely benign submissions but no case-control statistic.
- No exact variant match was identified in the reviewed BRCA2 multifactorial/posterior probability tables used for PS4 support.
Still missing
- A case-control dataset or expert-panel quantitative evidence showing significant enrichment in affected individuals would be needed for PS4.
Sources
PM3 No evidence was identified that this variant was observed in trans with another BRCA2 variant in a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM3 Fanconi anemia in-trans rule
Evidence considered
- ENIGMA BRCA2 PM3 is limited to BRCA2-related Fanconi anemia contexts.
- No such proband-level data were identified.
Still missing
- Documented trans observations in BRCA2-related Fanconi anemia cases would be needed for PM3.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No quantitative co-segregation data for this variant were identified, so PP1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP1 quantitative segregation rule
Evidence considered
- No variant-specific segregation likelihood ratio was identified in the reviewed BRCA2 supporting datasets.
Still missing
- A family-based segregation likelihood ratio meeting ENIGMA thresholds would be needed for PP1.
Sources
PP4 No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support PP4 at this time. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP4 clinical-history LR rule
Evidence considered
- No c.2259T>C entry was identified in the BRCA2 clinical-history LR workbook.
Still missing
- A variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds would be needed for PP4.
Sources
BS2 No evidence was identified that this variant was observed under the ENIGMA BRCA2 unaffected or non-Fanconi-anemia conditions required for BS2 point assignment, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS2 point-based rule
Evidence considered
- ENIGMA BRCA2 BS2 requires specific point-based observations in the absence of Fanconi anemia features.
- No such data were identified.
Still missing
- Documented qualifying observations under the BRCA2 BS2 point framework would be needed for BS2.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS3 No calibrated BRCA2 functional or RNA assay demonstrating no damaging effect for this exact variant was identified, so BS3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS3 calibrated functional evidence rule
Evidence considered
- No exact c.2259T>C or p.(F753=) match was identified in the BRCA2 VCEP functional table.
- No exact variant-specific benign functional entry was identified in the reviewed supporting workbook.
Still missing
- A variant-specific calibrated functional or transcript assay showing no damaging effect would be needed for BS3.
Sources
BS4 No quantitative non-segregation data for this variant were identified, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BS4 quantitative non-segregation rule
Evidence considered
- No variant-specific non-segregation likelihood ratio was identified in the reviewed BRCA2 supporting datasets.
Still missing
- A family-based likelihood ratio showing lack of segregation and meeting ENIGMA thresholds would be needed for BS4.
Sources
BP5 No exact match for this variant was identified in the BRCA2 clinical-history likelihood-ratio table, so there is no quantitative multifactorial clinical-history evidence to support BP5 at this time. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP5 clinical-history LR rule
Evidence considered
- No c.2259T>C entry was identified in the BRCA2 clinical-history LR workbook.
Still missing
- A variant-specific clinical-history likelihood ratio at or below ENIGMA BP5 thresholds would be needed for BP5.
Sources
BP7 SpliceAI predicts no splice effect (max delta score 0.00), but no variant-specific RNA study showing normal transcript processing was identified, and this outside-domain synonymous variant does not meet the ENIGMA BP7 supporting rule that is limited to silent variants inside clinically important domains with BP4 met. BP7 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 supporting and BP7_RNA rules
Evidence considered
- SpliceAI max delta score is 0.00.
- No exact variant-specific benign RNA/functional entry was identified in the reviewed BRCA2 VCEP functional table.
- Codon 753 is outside the ENIGMA BRCA2 clinically important domains aa 10-40 and aa 2481-3186.
Still missing
- A variant-specific RNA assay showing no abnormal splicing would be needed to consider BP7_RNA.
- If future evidence placed the variant within a qualifying BP7 supporting scenario
- that rule could be revisited.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThe ENIGMA BRCA2 specification marks de novo evidence as not applicable for this gene framework, so PS2 was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PS2 is listed as not applicable in the BRCA2 expert specification.
Sources
PM1 N/AThe ENIGMA BRCA2 specification marks PM1 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PM1 is listed as not applicable in the BRCA2 expert specification.
Sources
PM4 N/AThe ENIGMA BRCA2 specification marks PM4 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PM4 is listed as not applicable in the BRCA2 expert specification.
Sources
PM5 N/AIn the ENIGMA BRCA2 framework, PM5 is repurposed for truncating or protein-termination-codon logic rather than classic same-residue missense comparison, and this synonymous variant does not meet that use case. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PM5_PTC rule only
Evidence considered
- PM5 candidate review marked the BRCA2 PM5 mode as PTC-specific.
- This variant is synonymous and not a truncating variant.
Sources
cspec ↗pm5_candidates
PM6 N/AThe ENIGMA BRCA2 specification marks assumed de novo evidence as not applicable, so PM6 was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PM6 is listed as not applicable in the BRCA2 expert specification.
Sources
PP2 N/AThe ENIGMA BRCA2 specification marks PP2 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PP2 is listed as not applicable in the BRCA2 expert specification.
Sources
PP5 N/AThe ENIGMA BRCA2 specification marks PP5 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- PP5 is listed as not applicable in the BRCA2 expert specification.
Sources
BP2 N/AThe ENIGMA BRCA2 specification marks BP2 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- BP2 is listed as not applicable in the BRCA2 expert specification.
Sources
BP3 N/AThe ENIGMA BRCA2 specification marks BP3 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- BP3 is listed as not applicable in the BRCA2 expert specification.
Sources
BP6 N/AThe ENIGMA BRCA2 specification marks BP6 as not applicable, so this criterion was not applied. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA2 specification
Evidence considered
- BP6 is listed as not applicable in the BRCA2 expert specification.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.2259T>C
- Protein (HGVS p.)
- NP_000050.3:p.(Phe753=)
- GRCh38
- chr13:32336614 T>C
- GRCh37
- chr13:32910751 T>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
—
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 / 1,614,118 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,118 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,180,000 | 2.5e-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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.8586e-06; MAF= 0.00019%, 3/1614118 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54237e-06; MAF= 0.00025%, 3/1180000 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no meaningful splice effect for this synonymous variant (max delta score 0.00), which is below the ENIGMA BRCA2 PP3 splice threshold of 0.2, so PP3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 PP3 splice threshold SpliceAI >=0.2
Evidence considered
- SpliceAI DS_AG 0.0
- DS_AL 0.0
- DS_DG 0.0
- DS_DL 0.0
- max delta 0.00.
Still missing
- Variant-specific RNA data would be needed if a splice effect remained clinically suspected despite the negative prediction.
Sources
BP4 SpliceAI predicts no splice effect (max delta score 0.00), but the ENIGMA BRCA2 BP4 rule for silent variants is limited to synonymous variants inside clinically important domains; this variant is at codon 753, outside those domains, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP4 silent-variant domain rule
Evidence considered
- SpliceAI max delta score is 0.00.
- Codon 753 is outside the ENIGMA BRCA2 clinically important domains aa 10-40 and aa 2481-3186.
Sources
BP7 SpliceAI predicts no splice effect (max delta score 0.00), but no variant-specific RNA study showing normal transcript processing was identified, and this outside-domain synonymous variant does not meet the ENIGMA BP7 supporting rule that is limited to silent variants inside clinically important domains with BP4 met. BP7 was therefore not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA2 BP7 supporting and BP7_RNA rules
Evidence considered
- SpliceAI max delta score is 0.00.
- No exact variant-specific benign RNA/functional entry was identified in the reviewed BRCA2 VCEP functional table.
- Codon 753 is outside the ENIGMA BRCA2 clinically important domains aa 10-40 and aa 2481-3186.
Still missing
- A variant-specific RNA assay showing no abnormal splicing would be needed to consider BP7_RNA.
- If future evidence placed the variant within a qualifying BP7 supporting scenario
- that rule could be revisited.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
3 / 1,614,118 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/516910/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32910751-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32336614-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.2259…
- OncoKB ↗www.oncokb.org/gene/BRCA2/F753=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.2259T%3EC
- 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= 1.8586e-06; MAF= 0.00019%, 3/1614118 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54237e-06; MAF= 0.00025%, 3/1180000 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 516910)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.