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LYFE SCIENCES
Project: HERA
NM_007294.3:c.68_69del
p.Glu23ValfsTer17  ·  BRCA1
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Classification rationale
1

The BRCA1 NM_007294.3:c.68_69del (NP_009225.1:p.(Glu23ValfsTer17); p.(E23Vfs*17)) variant has been reported in ClinVar as Pathogenic with expert-panel review and is also curated in OncoKB as a loss-of-function BRCA1 variant.

clinvar ↗ oncokb ↗
2

In gnomAD, the variant is present overall at AF 0.000205352 in v2.1 and 0.00011848 in v4.1, with non-founder grpmax FAF values of 5.395e-05 and 2.478e-05 respectively; this is above the ENIGMA BS1 Supporting threshold of 0.00002 but below the BA1 threshold of 0.001.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This 2-bp deletion causes an early frameshift with a predicted premature stop, and the ENIGMA BRCA1 specification assigns PVS1 for exon 2 truncating variants and PM5_Strong for protein-truncating variants in exon 2.

cspec ↗
4

BRCA1 clinical-history likelihood analysis lists the equivalent c.68_69delAG variant in 202 probands with LR 1.145935772193482e+20, far above the ENIGMA PP4 Very Strong threshold of 350.

PMID:31853058 ↗ cspec ↗
5

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), which does not create a separate PP3 or BP4 code for this protein-truncating frameshift under the ENIGMA BRCA1 rules.

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
  • —
Rule
—
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= 0.000205352; MAF= 0.02054%, 58/282442 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00405093; MAF= 0.40509%, 42/10368 alleles, homozygotes = 0); grpmax FAF= 5.395e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.00011848; MAF= 0.01185%, 191/1612084 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.0041585; MAF= 0.41585%, 123/29578 alleles, homozygotes = 0); grpmax FAF= 2.478e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (79 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 17662)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58786277, n = 5 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueE23
Hotspots ↗