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
BRCA2
Final classification
Pathogenic
BRCA2 c.8023A>G · p.Ile2675Val
BRCA2
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 ↗
Gene diagram
· NM_000059.3 · variants mapped to exon structure
BRCA2
NM_000059.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:17924331
Found
Structured finding pending for this record — see source link.
Applied to
→PP1 supports · met
→PP4 supports · met
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