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.1 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.2 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.3 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 0.1.4
BRCA2
Final classification
Pathogenic
BRCA2 c.8023A>G · p.Ile2675Val
BRCA2
The BRCA2 c.8023A>G (p.Ile2675Val) variant has not been observed in 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.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework.
Classification rationale
PP1PP3PP5
Pathogenic
BRCA2 c.8023A>G
PP1 + PP3 + PP5
→
Pathogenic
3
vcep_humu_40_1557_s001PMID:18424508 ↗PMID:22505045 ↗
Gene diagram
· NM_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.
Sources & reference links