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
BRCA1
Final classification
Pathogenic
BRCA1 c.68_69del · p.Glu23ValfsTer17
BRCA1
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
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 6 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 (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.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links