About BRCA2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA2 c.8023A>G, p.(Ile2675Val)
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
PP1Very strong
PP1 · very strong
Quantitative co-segregation evidence supports pathogenicity. The BRCA2 multifactorial dataset reports a segregation likelihood ratio of 605.14 for this variant, which is above the ENIGMA PP1_Very Strong threshold of 350.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious splicing effect. SpliceAI predicts strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 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
1 / 1,614,050 alleles
gnomAD v4.1: 1 / 1,614,050 alleles. Recorded AF 6.19559e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98286e-06; MAF= 0.00040%, 1/251076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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 · 6 not met · 9 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.8023A>G (p.Ile2675Val) variant has not been observed in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.
This variant is present at very low frequency in gnomAD, with 1/251076 alleles in v2.1 and 1/1614050 alleles in v4.1; the highest observed population frequencies are 5.44e-05 in East Asian individuals in v2.1 and 2.23e-05 in East Asian individuals in v4.1, so the variant is rare but not absent from controls.
BRCA2 multifactorial data show strong pathogenic evidence for this variant, including a segregation likelihood ratio of 605.14 and a posterior probability of 0.999651, and multiple splicing studies reported complete 309-nt skipping of exon 18 with no full-length transcript detected from the variant allele.
Computational splicing analysis supports a deleterious effect, with a SpliceAI maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2 and well above the benign BP4 threshold of 0.1.
No criteria match.
Met · 3
PP1 Very strongQuantitative co-segregation evidence supports pathogenicity. The BRCA2 multifactorial dataset reports a segregation likelihood ratio of 605.14 for this variant, which is above the ENIGMA PP1_Very Strong threshold of 350. Details ▾Hide ▴
Rule
ENIGMA PP1; PP1_Very Strong if LR >= 350
Evidence considered
- Segregation LR 605.13969286 in the BRCA2 multifactorial dataset.
Still missing
- The underlying pedigrees were not independently reviewed in this pass.
Sources
cspec ↗vcep_humu_40_1557_s001
PP3 SupportingComputational evidence supports a deleterious splicing effect. SpliceAI predicts strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2. Details ▾Hide ▴
Rule
ENIGMA PP3 for predicted splicing with SpliceAI >= 0.2
Evidence considered
- SpliceAI max delta score 0.99.
Sources
Not met · 6 · evaluated, threshold not reached
PM2 This variant is not absent from controls. It is present in gnomAD v2.1 at 1/251076 alleles (AF 3.98e-06) and in gnomAD v4.1 at 1/1614050 alleles (AF 6.20e-07), so the ENIGMA PM2_Supporting requirement for absence from gnomAD is not met. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from controls
Evidence considered
- gnomAD v2.1 total AC 1/AN 251076.
- gnomAD v4.1 total AC 1/AN 1614050.
Sources
BA1 This variant does not meet the ENIGMA BA1 frequency threshold. The highest observed population frequency in gnomAD is 5.44e-05 in East Asian individuals in v2.1 and 2.23e-05 in East Asian individuals in v4.1, both well below the BA1 requirement of filter allele frequency greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BA1 requires FAF > 0.001
Evidence considered
- Highest observed AF 5.43833e-05 in gnomAD v2.1 East Asian.
- Highest observed AF 2.22836e-05 in gnomAD v4.1 East Asian.
Sources
BS1 The retrieved gnomAD records do not show a qualifying filter allele frequency for BS1, and the observed frequencies do not justify direct BS1 assignment from the available evidence. The highest observed population frequency is 5.44e-05 in gnomAD v2.1 East Asian and 2.23e-05 in gnomAD v4.1 East Asian, while group-max FAF was not available in the retrieved gnomAD outputs. Details ▾Hide ▴
Rule
ENIGMA BS1 uses FAF thresholds
Evidence considered
- Observed AF values were available
- FAF values were not populated.
Still missing
- Filter allele frequency was not available in the retrieved gnomAD records.
Sources
BS4 Available segregation data do not support lack of segregation. The BRCA2 multifactorial dataset reports a segregation likelihood ratio of 605.14 in favor of pathogenicity, which is far above the BS4 thresholds that require a likelihood ratio of 0.48 or lower against pathogenicity. Details ▾Hide ▴
Rule
ENIGMA BS4 requires LR <= 0.48, <= 0.23, or <= 0.05 depending on strength
Evidence considered
- Segregation LR 605.13969286.
Sources
cspec ↗vcep_humu_40_1557_s001
BP1 This missense variant does not meet BP1. It lies within the BRCA2 DNA-binding domain and SpliceAI predicts splice disruption with a score of 0.99, whereas ENIGMA BP1_Strong requires a variant outside a clinically important domain and no predicted splicing impact with SpliceAI 0.1 or lower. Details ▾Hide ▴
Rule
ENIGMA BP1_Strong
Evidence considered
- Protein position 2675 is within the BRCA2 DNA-binding domain.
- SpliceAI max delta score 0.99.
Sources
BP4 This variant does not meet BP4 because computational evidence predicts splice disruption. SpliceAI gives a maximum delta score of 0.99, which is above the ENIGMA BP4 requirement for no predicted splice impact with SpliceAI 0.1 or lower. Details ▾Hide ▴
Rule
ENIGMA BP4 requires SpliceAI <= 0.1
Evidence considered
- SpliceAI max delta score 0.99.
Sources
Not assessed · 9 · no assessment recorded
PVS1 Multiple RNA studies reported complete 309-nt skipping of BRCA2 exon 18 with no full-length transcript detected from the variant allele, but this exonic substitution is outside the default generic null-variant buckets and no explicit ENIGMA RNA-based PVS1 strength assignment for this specific variant was identified in the retrieved materials. Manual review is needed to determine whether the observed splicing effect warrants PVS1(RNA) and at what strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 and PVS1(RNA) framework
Evidence considered
- BRCA2 loss of function is an established disease mechanism in the ENIGMA framework.
- Splicing studies reported complete exon 18 skipping for c.8023A>G.
Still missing
- No explicit variant-specific ENIGMA PVS1(RNA) code assignment was identified in the retrieved materials.
- RNA evidence needs manual mapping to the ENIGMA Figure 1B/Appendix E framework.
Sources
PS1 No retrieved evidence identified a different BRCA2 variant with the same protein change or the same established splicing consequence that has already been classified as pathogenic or likely pathogenic for PS1 application. Details ▾Hide ▴
Rule
ENIGMA PS1
Evidence considered
- ENIGMA PS1 requires a previously classified variant with the same protein or splicing consequence.
Still missing
- No variant-specific PS1 comparison record was identified in the retrieved evidence.
Sources
PS3 Available studies for this variant assess abnormal splicing rather than a calibrated protein-function assay entry in the ENIGMA functional table. Under the BRCA2 specification, mRNA-only damaging evidence is considered under PVS1(RNA) rather than PS3. Details ▾Hide ▴
Rule
ENIGMA PS3
Evidence considered
- Table 9 contained no variant-specific PS3 entry.
- RNA studies reported exon 18 skipping.
Still missing
- No variant-specific PS3 assignment was identified in ENIGMA Table 9.
- Protein-level calibrated functional evidence was not identified for this variant in the retrieved materials.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:18424508 ↗PMID:22505045 ↗
PS4 A qualifying case-control comparison was not identified. In the BRCA2 multifactorial dataset, the case-control likelihood ratio for this variant was not reported, so the retrieved evidence does not establish the ENIGMA PS4 requirement for significantly increased prevalence in affected individuals versus controls. Details ▾Hide ▴
Rule
ENIGMA PS4
Evidence considered
- Case-control LR field was blank in the BRCA2 multifactorial dataset.
Still missing
- No qualifying case-control odds ratio with confidence interval was identified.
- The multifactorial dataset did not provide a usable case-control LR for this variant.
Sources
PM3 No evidence was identified for this variant in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 could not be evaluated. Details ▾Hide ▴
Rule
ENIGMA PM3
Evidence considered
- ENIGMA PM3 is restricted to BRCA2-related Fanconi anemia contexts.
Still missing
- No Fanconi anemia phenotype data were identified.
- No phase-confirmed in trans observations were identified.
Sources
PP4 No variant-specific clinical-history likelihood ratio was identified in the BRCA2 clinical-history table, so PP4 could not be assigned from the retrieved evidence. Legacy multifactorial data exist, but applying those here as PP4 would risk double counting with segregation-based evidence. Details ▾Hide ▴
Rule
ENIGMA PP4 based on multifactorial clinical-history LR
Evidence considered
- No match for c.8023A>G was identified in the BRCA2 clinical-history LR workbook.
Still missing
- No matching row was identified in the BRCA2 clinical-history LR table.
- A non-overlapping clinical-history LR suitable for PP4 was not established.
Sources
BS2 No proband-level evidence was identified to show this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 could not be evaluated. Details ▾Hide ▴
Rule
ENIGMA BS2
Evidence considered
- ENIGMA BS2 requires specific proband-based point assignment.
Still missing
- No qualifying proband data were identified.
- No BS2 point assignment data were identified.
Sources
BS3 No variant-specific benign functional assignment was identified in the ENIGMA functional assay table. Available studies for this variant show abnormal splicing rather than normal function, so BS3 is not supported by the retrieved evidence. Details ▾Hide ▴
Rule
ENIGMA BS3
Evidence considered
- Table 9 contained no BS3 entry for c.8023A>G.
- Splicing studies reported complete exon 18 skipping rather than a benign result.
Still missing
- No variant-specific BS3 assignment was identified in ENIGMA Table 9.
Sources
BP5 No variant-specific clinical-history likelihood ratio in the benign direction was identified in the BRCA2 clinical-history table, so BP5 could not be assigned from the retrieved evidence. Details ▾Hide ▴
Rule
ENIGMA BP5 based on multifactorial clinical-history LR
Evidence considered
- No match for c.8023A>G was identified in the BRCA2 clinical-history LR workbook.
Still missing
- No matching row was identified in the BRCA2 clinical-history LR workbook.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ANo de novo framework is used for BRCA2 in this specification for this case, and no confirmed de novo data were identified. Details ▾Hide ▴
Rule
ENIGMA PS2
Evidence considered
- PS2 is marked not applicable in the BRCA2 specification for this case context.
Sources
PM1 N/APM1 is not used for BRCA2 in this specification. Details ▾Hide ▴
Rule
ENIGMA PM1
Evidence considered
- PM1 is marked not applicable in the BRCA2 specification.
Sources
PM4 N/APM4 is not used for BRCA2 in this specification. Details ▾Hide ▴
Rule
ENIGMA PM4
Evidence considered
- PM4 is marked not applicable in the BRCA2 specification.
Sources
PM5 N/AIn this BRCA2 specification, PM5 is defined for protein-terminating variants in eligible exons. This variant is a single-nucleotide substitution annotated at the protein level as p.(Ile2675Val), so PM5 is not applicable under the retrieved BRCA2 rule set. Details ▾Hide ▴
Rule
ENIGMA PM5_PTC
Evidence considered
- ENIGMA PM5 rule retrieved for BRCA2 addresses PTC variants.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not used for BRCA2 in this specification for this case context. Details ▾Hide ▴
Rule
ENIGMA PM6
Evidence considered
- PM6 is marked not applicable in the BRCA2 specification.
Sources
PP2 N/APP2 is not used for BRCA2 in this specification. Details ▾Hide ▴
Rule
ENIGMA PP2
Evidence considered
- PP2 is marked not applicable in the BRCA2 specification.
Sources
BP2 N/ABP2 is not used for BRCA2 in this specification. Details ▾Hide ▴
Rule
ENIGMA BP2
Evidence considered
- BP2 is marked not applicable in the BRCA2 specification.
Sources
BP3 N/ABP3 is not used for BRCA2 in this specification. Details ▾Hide ▴
Rule
ENIGMA BP3
Evidence considered
- BP3 is marked not applicable in the BRCA2 specification.
Sources
BP6 N/ABP6 is not used in this framework. Details ▾Hide ▴
Rule
ENIGMA BP6
Evidence considered
- BP6 is marked not applicable in the BRCA2 specification.
Sources
BP7 N/ABP7 is intended for silent or intronic variants, or for specific RNA-based benign scenarios. This is a missense variant with predicted and observed splice disruption, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7
Evidence considered
- Missense variant with SpliceAI 0.99 and observed exon 18 skipping.
Sources
Identifiers
- Gene
- BRCA2
- Transcript
- NM_000059.4
- Coding (HGVS c.)
- NM_000059.4:c.8023A>G
- Protein (HGVS p.)
- NP_000050.3:p.(Ile2675Val)
- GRCh38
- chr13:32363225 A>G
- GRCh37
- chr13:32937362 A>G
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 / 1,614,050 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,076 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,050 alleles · 0 hom
| East Asian1 / 44,876 | 2.2e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,076 alleles · 0 hom
| East Asian1 / 18,388 | 5.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19559e-07; MAF= 0.00006%, 1/1614050 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22836e-05; MAF= 0.00223%, 1/44876 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98286e-06; MAF= 0.00040%, 1/251076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious splicing effect. SpliceAI predicts strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2. Details ▾Hide ▴
Rule
ENIGMA PP3 for predicted splicing with SpliceAI >= 0.2
Evidence considered
- SpliceAI max delta score 0.99.
Sources
BP4 This variant does not meet BP4 because computational evidence predicts splice disruption. SpliceAI gives a maximum delta score of 0.99, which is above the ENIGMA BP4 requirement for no predicted splice impact with SpliceAI 0.1 or lower. Details ▾Hide ▴
Rule
ENIGMA BP4 requires SpliceAI <= 0.1
Evidence considered
- SpliceAI max delta score 0.99.
Sources
BP7 N/ABP7 is intended for silent or intronic variants, or for specific RNA-based benign scenarios. This is a missense variant with predicted and observed splice disruption, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7
Evidence considered
- Missense variant with SpliceAI 0.99 and observed exon 18 skipping.
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
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 / 1,614,050 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/52475/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/13-32937362-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr13-32363225-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000059.4%3Ac.8023…
- OncoKB ↗www.oncokb.org/gene/BRCA2/I2675V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA2+c.8023A%3EG
- 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= 6.19559e-07; MAF= 0.00006%, 1/1614050 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22836e-05; MAF= 0.00223%, 1/44876 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98286e-06; MAF= 0.00040%, 1/251076 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43833e-05; MAF= 0.00544%, 1/18388 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (14 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.