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
Final classification
Pathogenic
PP1PP3PP5
BRCA2
c.8023A>G
p.Ile2675Val
This variant
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 ↗
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_000059.4 · variants mapped to exon structure
BRCA2
NM_000059.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PP1
very strong
review
Pathogenic
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.
Segregation LR 605.13969286 in the BRCA2 multifactorial dataset.
PP3
supporting
Pathogenic
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.
SpliceAI max delta score 0.99.
Assessed · not applied
· 6 not met · 9 not assessed
Pathogenic
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.
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.
PS3
Available studies for this variant assess abnormal splicing rather than a calibrated protein-function assay entry in the ENIGMA functional table.
PS4
A qualifying case-control comparison was not identified.
PM2
This variant is not absent from controls.
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.
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.
Benign
BA1
This variant does not meet the ENIGMA BA1 frequency threshold.
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.
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.
BS3
No variant-specific benign functional assignment was identified in the ENIGMA functional assay table.
BS4
Available segregation data do not support lack of segregation.
BP1
This missense variant does not meet BP1.
BP4
This variant does not meet BP4 because computational evidence predicts splice disruption.
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.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
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