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.1 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 0.001.2 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 2.3 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 350.4 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.5
Final classification
Pathogenic
PVS1PM5PP4PP5BS1
BRCA1
c.68_69del
p.Glu23ValfsTer17
This variant
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.
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 with ENIGMA conflicting-evidence point system).
Classification rationale
PVS1PM5PP4PP5
BS1
Pathogenic
BRCA1 c.68_69del
PVS1 + PM5 + PP4 + PP5 + BS1
→
Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18
4
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗cspec ↗
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_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 8 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 · 5
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a 2-bp deletion in BRCA1 exon 2 that causes an early frameshift, NP_009225.1:p.(Glu23ValfsTer17) (p.(E23Vfs*17)), with a premature termination codon. Loss of function is an established disease mechanism for BRCA1, and the ENIGMA BRCA1 specification assigns PVS1 to exon 2 protein-truncating variants.
BRCA1 loss of function is established in the applicable ENIGMA framework.The variant is a frameshift with predicted p.(Glu23ValfsTer17).ENIGMA Table 4 assigns PVS1 to BRCA1 exon 2 protein-truncating variants.
PM5
strong
Pathogenic
In the ENIGMA BRCA1 framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense comparison. This frameshift creates a premature termination codon in BRCA1 exon 2, and ENIGMA Table 4 and Supplementary Table 1 assign PM5_Strong for exon 2 protein-truncating variants.
PM5 candidate artifact indicates gene-specific PTC logic rather than classic same-residue PM5.ENIGMA Table 4 lists BRCA1 exon 2 PTC variants as PM5_Strong (PTC).Supplementary Table 1 shows Strong PM5_PTC weighting for BRCA1 exon 2.
PP4
very strong
Pathogenic
In the BRCA1 clinical-history likelihood-ratio dataset, this variant is listed as c.68_69delAG in 202 probands with LR 1.145935772193482e+20. This value is far above the ENIGMA PP4 Very Strong threshold of 350, supporting a strong pathogenic clinical-history signal.
Clinical-history LR workbook contains BRCA1 c.68_69delAG.Observed LR is 1.145935772193482e+20 in 202 probands.ENIGMA PP4 Very Strong threshold is LR >= 350.
BS1
supporting
Benign
The non-founder filter allele frequency is above the ENIGMA BS1 Supporting threshold of 0.00002 and does not exceed the BS1 Strong threshold of 0.0001. The observed grpmax FAF is 5.395e-05 in gnomAD v2.1 and 2.478e-05 in gnomAD v4.1, so BS1 is met at Supporting strength.
gnomAD v2.1 grpmax FAF 5.395e-05.gnomAD v4.1 grpmax FAF 2.478e-05.Both values are >0.00002 and <=0.0001.
Assessed · not applied
· 3 not met · 5 not assessed
Pathogenic
PS4
This variant has been reported as pathogenic in ClinVar, but no directly extracted case-control odds ratio or p-value meeting the ENIGMA PS4 thresholds was identified in the reviewed sources.
PM2
This variant is not absent from population databases.
PM3
ENIGMA applies PM3 in the setting of BRCA1- or BRCA2-related Fanconi anemia with qualifying biallelic observations.
PP1
No quantitative segregation analysis or likelihood ratio meeting the ENIGMA PP1 thresholds was identified for this variant in the reviewed sources.
Benign
BA1
The non-founder filter allele frequency does not exceed the ENIGMA BA1 threshold of 0.001.
BS2
ENIGMA applies BS2 using point-based observations in individuals without Fanconi anemia features.
BS4
No quantitative non-segregation analysis meeting the ENIGMA BS4 thresholds was identified for this variant in the reviewed sources.
BP5
The available clinical-history likelihood evidence is strongly in the pathogenic direction rather than the benign direction.
N/A · 15
PS1 · PS2 · PS3 · PM1 · PM4 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP3 · BP4 · 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= 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.012%
· 191 / 1,612,084
0 hom · FAF 0.0025%
0 hom · FAF 0.0025%
Ashkenazi Jewish 123 / 29,578 |
0.42% |
Remaining individuals 20 / 62,394 |
0.032% |
Middle Eastern 1 / 6,078 |
0.016% |
South Asian 5 / 91,044 |
0.0055% |
Admixed American 3 / 59,996 |
0.005% |
European (non-Finnish) 39 / 1,178,366 |
0.0033% |
+ 4 not observed (European (Finnish), Amish, East Asian, African/African American)
gnomAD v2.1
0.021%
· 58 / 282,442
0 hom · FAF 0.0054%
0 hom · FAF 0.0054%
Ashkenazi Jewish 42 / 10,368 |
0.41% |
South Asian 4 / 30,608 |
0.013% |
European (non-Finnish) 11 / 128,780 |
0.0085% |
Admixed American 1 / 35,440 |
0.0028% |
+ 4 not observed (African/African American, East Asian, European (Finnish), Remaining individuals)
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
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. 10 further PMIDs triaged but not cited — see Sources & references.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
very strong
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
23867111 ↗
A high-throughput functional complementation assay for classification of BRCA1 missense variants.
ONCOKB
9145676 ↗
The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.
ONCOKB
14729053 ↗
Cytoplasmic mislocalization of BRCA1 caused by cancer-associated mutations in the BRCT domain.
ONCOKB
15569676 ↗
The BRCA1 RING and BRCT domains cooperate in targeting BRCA1 to ionizing radiation-induced nuclear foci.
ONCOKB
26246475 ↗
Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes.
ONCOKB
27454287 ↗
BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1.
ONCOKB
11466700 ↗
The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR
30122538 ↗
Evaluation of Recipients of Positive and Negative Secondary Findings Evaluations in a Hybrid CLIA-Research Sequencing Pilot.
CLINVAR