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LYFE SCIENCES
Project: HERA
NM_000059.4:c.8023A>G
p.Ile2675Val  ·  BRCA2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

PMID:18424508 ↗ PMID:22505045 ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueI2675
Hotspots ↗