The BRCA2 c.8023A>G (p.Ile2675Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.1 This variant is present at very low frequency in population databases, with 1/251076 alleles in gnomAD v2.1 and 1/1614050 alleles in gnomAD v4.1, with no homozygotes reported.2 In published splice studies summarized in the ENIGMA-aligned BRCA resource, this variant generated a strong donor site within exon 18 and was associated with a predominant exon 18-deleted transcript; the multifactorial dataset also shows a segregation likelihood ratio of 605.14 and an overall posterior probability of pathogenicity of 0.999651.3 Computational evidence supports splice disruption, with SpliceAI 0.99 exceeding the BRCA2 ENIGMA PP3 threshold of 0.2; REVEL is high at 0.88, while BayesDel is 0.086 and does not support a benign BP4 call because SpliceAI is above the BP4 threshold of 0.1.4
Final classification
Pathogenic
PP1PP3PP4PP5
BRCA2
c.8023A>G
p.Ile2675Val
This variant
The BRCA2 c.8023A>G (p.Ile2675Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override)
Classification rationale
PP1PP3PP4PP5
Pathogenic
BRCA2 c.8023A>G
PP1 + PP3 + PP4 + PP5
→
Pathogenic
3
vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18PMID:18424508 ↗PMID:22505045 ↗
4
spliceai ↗revelbayesdelcspec ↗
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.
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PP1
very strong
review
Pathogenic
This variant shows strong segregation with disease. The quantitative segregation likelihood ratio is 605.14, which is above the ENIGMA PP1_Very Strong threshold of 350.
Segregation LR 605.13969286 for BRCA2 c.8023A>G in the Parsons/Easton multifactorial dataset.
PP3
supporting
review
Pathogenic
Computational evidence supports a splice-altering effect. SpliceAI predicts a strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact.
SpliceAI max delta 0.99.REVEL 0.88.BayesDel 0.0862004.
PP4
supporting
review
Pathogenic
Clinical-history evidence is in the pathogenic direction. The family-history likelihood ratio is 2.88, which is above the ENIGMA PP4 threshold of 2.08 and below the moderate threshold of 4.3, supporting PP4 at supporting strength.
Family history LR 2.8834980449 for BRCA2 c.8023A>G in the multifactorial dataset.
Assessed · not applied
· 11 not met · 4 not assessed
Pathogenic
PVS1
RNA studies identified a predominant in-frame exon 18 deletion transcript for this variant, but the available evidence does not show a canonical null allele or provide a clear ENIGMA PVS1(RNA) weight for this specific event.
PS1
No qualifying previously classified pathogenic or likely pathogenic comparator with the same proven protein or splicing consequence was identified for PS1 application.
PS3
Published evidence shows abnormal splicing rather than a calibrated protein-function assay result for this variant.
PS4
Multifactorial pathogenic evidence was identified for this variant, but no direct case-control odds ratio with p-value meeting the BRCA2 ENIGMA PS4 threshold was extracted from the retrieved evidence.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia.
Benign
BA1
Population frequency does not reach the ENIGMA BA1 threshold.
BS1
This variant is present at a very low frequency in gnomAD, but the retrieved data did not provide a qualifying ENIGMA filter allele frequency value for BS1 assessment.
BS2
No qualifying observations were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 framework.
BS3
Available functional evidence does not show normal or retained function.
BS4
Available segregation evidence is in favor of pathogenicity rather than lack of segregation.
BP1
This missense variant does not meet BRCA2 ENIGMA BP1 because it is not a low-risk missense change without splice concern.
BP4
Computational evidence does not support BP4.
BP5
Available clinical-history evidence is not in the benign direction.
BP7
This is a missense variant with predicted splice impact rather than a synonymous or eligible intronic change with no splice effect, so BP7 is not met.
N/A · 9
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
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).
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,050
0 hom
0 hom
East Asian 1 / 44,876 |
0.0022% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 251,076
0 hom
0 hom
East Asian 1 / 18,388 |
0.0054% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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). (ClinVarID = 52475)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). REVEL score = 0.88. BayesDel score = 0.0862004.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 9 further PMIDs triaged but not cited — see Sources & references.
Easton et al. 2007 BRCA1/2 multifactorial likelihood assessment
Found
Structured finding pending for this record — see source link.
Applied to
→PP1
very strong
→PP4
supporting
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
18424508 ↗
Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.
ONCOKB
15290653 ↗
Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2.
CLINVAR
16489001 ↗
Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.
CLINVAR
22505045 ↗
Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.
CLINVAR
23108138 ↗
A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
29192238 ↗
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals.
CLINVAR