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
BRCA1
Final classification
Pathogenic
BRCA1 c.68_69del · p.Glu23ValfsTer17
BRCA1
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 ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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
6papers 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.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID vcep_pmid_31853058_brca1_clinical_history_lr
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID vcep_pmid_31853058_li_2020_geneticsinmedicine
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
PMID vcep_specifications_table4_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
→PVS1 supports · met
PMID vcep_specifications_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→BS1 supports · met
→PM5 supports · met
→PP5 supports · met
→PVS1 supports · met
PMID vcep_supplementarytables_v1_2_2024_11_18
Found
Structured finding pending for this record — see source link.
Applied to
→PM5 supports · met
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