The BRCA1 NM_007294.4:c.4065_4068del (NP_009225.1:p.(Asn1355LysfsTer10), p.(N1355Kfs*10)) variant has been reported in ClinVar as Pathogenic by the ENIGMA expert panel and by multiple clinical laboratories.1 This variant is present at very low frequency in gnomAD v2.1 (3/250844 alleles; AF 1.19596e-05, 0.00120%; grpmax FAF 2.93e-06), which is below the BRCA1 BA1 and BS1 thresholds but means the variant is not absent from controls, so PM2 is not met.2 The BRCA1 clinical-history likelihood-ratio dataset lists this deletion as c.4065_4068delTCAA in 37 probands with LR 6590.9969, supporting pathogenic clinical-history evidence under the ENIGMA BRCA1 framework.3 This frameshift lies in BRCA1 exon 10(11) and predicts a premature stop codon at residue 1364; the ENIGMA BRCA1 exon-specific Table 4 supports PVS1 and PM5_Strong (PTC) for truncating variants in this exon.4
BRCA1
Final classification
Pathogenic
BRCA1 c.4065_4068del · p.Asn1355LysfsTer10
BRCA1
The BRCA1 NM_007294.4:c.4065_4068del (NP_009225.1:p.(Asn1355LysfsTer10), p.(N1355Kfs*10)) variant has been reported in ClinVar as Pathogenic by the ENIGMA expert panel and by multiple clinical laboratories.
ENIGMA BRCA1/BRCA2 Specification v1.2 final-classification framework (Table 3 override captured in final_classification_framework; ACMG/AMP 2015 with ENIGMA adaptations).
Classification rationale
PVS1PM5PP4PP5
Pathogenic
BRCA1 c.4065_4068del
PVS1 + PM5 + PP4 + PP5
→
Pathogenic
3
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗vcep_specifications_v1_2_2024_11_18
4
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 · 4 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= 3.28469e-05; MAF= 0.00328%, 53/1613548 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.1529e-05; MAF= 0.00415%, 49/1179898 alleles, homozygotes = 0); grpmax FAF= 3.179e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.19596e-05; MAF= 0.00120%, 3/250844 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.28106e-05; MAF= 0.00328%, 1/30478 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0033%
· 53 / 1,613,548
0 hom · FAF 0.0032%
0 hom · FAF 0.0032%
European (non-Finnish) 49 / 1,179,898 |
0.0042% |
South Asian 3 / 90,982 |
0.0033% |
East Asian 1 / 44,886 |
0.0022% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 250,844
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
South Asian 1 / 30,478 |
0.0033% |
European (non-Finnish) 2 / 113,544 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (51 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 17674)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely 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; COSV99066383, n = 2 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.
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links
Triaged references · 10 PMIDs not cited in assessment
12947386 ↗
Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.
ONCOKB
20608970 ↗
BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.
ONCOKB
10699917 ↗
Detection of BRCA1 and BRCA2 mutations in breast cancer families by a comprehensive two-stage screening procedure.
CLINVAR
11802209 ↗
Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population.
CLINVAR
14757871 ↗
Haplotype and cancer risk analysis of two common mutations, BRCA1 4184del4 and BRCA2 2157delG, in high risk northwest England breast/ovarian families.
CLINVAR
17018160 ↗
Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India.
CLINVAR
21559243 ↗
Breast and Ovarian Cancer Risk due to Prevalence of BRCA1 and BRCA2 Variants in Pakistani Population: A Pakistani Database Report.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR