The BRCA1 c.68_69del (p.Glu23ValfsTer17; p.E23Vfs*17) variant is reported in ClinVar as Pathogenic, including expert-panel classification by ClinGen ENIGMA, and is also described by OncoKB as an oncogenic loss-of-function alteration.1 This variant is present in population databases, with gnomAD v2.1 AF 0.000205352 (58/282442 alleles) and gnomAD v4.1 AF 0.00011848 (191/1612084 alleles); the observed filter allele frequencies of 5.395e-05 in v2.1 and 2.478e-05 in v4.1 are below the BA1 threshold of 0.001 but within the ENIGMA BS1_Supporting range above 0.00002 and less than or equal to 0.0001.2 ENIGMA functional data assign PS3 Strong to this variant, with calibrated assay evidence showing a damaging effect consistent with a deleterious control profile.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which is consistent with the primary effect being protein truncation rather than splice disruption.4 This early exon 2 frameshift introduces a premature termination codon at p.Glu23ValfsTer17, and ENIGMA exon-level rules support PVS1 at Very Strong strength and PM5 for protein-truncating variants in this exon.5
Final classification
Pathogenic
PVS1PS3PM5PP4PP5BS1
BRCA1
c.68_69del
p.Glu23ValfsTer17
This variant
The BRCA1 c.68_69del (p.Glu23ValfsTer17; p.E23Vfs*17) variant is reported in ClinVar as Pathogenic, including expert-panel classification by ClinGen ENIGMA, and is also described by OncoKB as an oncogenic loss-of-function alteration.
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 conflicting-evidence point system; pathogenic evidence totals 25 points (PVS1_Very Strong, PS3_Strong, PM5_Strong, PP4_Very Strong, PP5_Supporting) and benign evidence totals -1 point (BS1_Supporting), for a net score of 24.
Classification rationale
PVS1PS3PM5PP4PP5
BS1
Pathogenic
BRCA1 c.68_69del
PVS1 + PS3 + PM5 + PP4 + PP5 + BS1
→
Pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
5
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18
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_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 6 applied · 9 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 · 6
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a frameshift deletion in BRCA1 exon 2, predicted to cause p.(Glu23ValfsTer17). BRCA1 loss of function is an established disease mechanism, and ENIGMA Table 4 designates exon 2 protein-truncating variants for full-strength PVS1, so this evidence supports PVS1 at Very Strong strength.
NM_007294.4:c.68_69del is predicted as NP_009225.1:p.(Glu23ValfsTer17)Variant Validator places the change in exon 2BRCA1 PVS1 gene gate is eligible
PS3
strong
Pathogenic
This variant is listed in ENIGMA Table 9 as PS3 Strong based on a calibrated functional study that showed protein function similar to pathogenic control variants. This is consistent with OncoKB describing the variant as an oncogenic loss-of-function alteration.
ENIGMA Table 9 entry: BRCA1 c.68_69del p.(Glu23Valfs*17) PS3 StrongSupplementary Table 4: Functional impact - completeDeleterious-control
PM5
strong
Pathogenic
This frameshift creates a premature termination codon in BRCA1 exon 2. ENIGMA Table 4 designates exon 2 protein-truncating variants for PM5_Strong (PTC), so this variant meets PM5 at Strong strength.
Variant is a protein-truncating frameshift in exon 2ENIGMA Table 4 exon 2 PTC row: PM5_Strong (PTC)
PP4
very strong
Pathogenic
This variant has a BRCA1 clinical-history likelihood ratio of 1.145935772193482e+20 from 202 probands in the BRCA1 clinical-history dataset. This value is far above the ENIGMA PP4_Very Strong threshold of 350, so the clinical-history evidence strongly supports pathogenicity.
HGVS_Nucleotide c.68_69delAGN_Probands = 202LR = 1.145935772193482e+20
BS1
supporting
Benign
This variant is present above the ENIGMA BS1_Supporting population threshold but below the BS1 threshold. The gnomAD v2.1 filter allele frequency is 5.395e-05 and the gnomAD v4.1 filter allele frequency is 2.478e-05, which are above 0.00002 and below or equal to 0.0001, consistent with BS1 at Supporting strength.
gnomAD v2.1 grpmax FAF = 5.395e-05gnomAD v4.1 grpmax FAF = 2.478e-05ENIGMA BS1_Supporting threshold > 0.00002 and <= 0.0001
Assessed · not applied
· 4 not met · 5 not assessed
Pathogenic
PS4
This variant has been reported in disease databases, but no qualifying case-control analysis with p-value less than or equal to 0.05 and odds ratio greater than or equal to 4 was identified here.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant was observed with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia.
PP1
No quantitative co-segregation analysis for this variant was identified, so PP1 was not assessed.
Benign
BA1
Available population data do not meet the BA1 threshold.
BS2
No qualifying observations of this variant in individuals without features of BRCA1-related Fanconi anemia were identified for the ENIGMA BS2 point system, so BS2 was not assessed.
BS3
Available functional evidence does not support a benign effect.
BS4
No quantitative lack-of-segregation analysis for this variant was identified, so BS4 was not assessed.
BP5
The BRCA1 clinical-history likelihood ratio for this variant is 1.145935772193482e+20 from 202 probands, which is far above the benign BP5 thresholds and strongly favors pathogenicity.
N/A · 13
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · 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 (77 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Oncogenic
OncoKB classifies this variant as Oncogenic; biological effect: 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 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.
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