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
Final classification
Pathogenic
PVS1PM5PP4PP5
BRCA1
c.4065_4068del
p.Asn1355LysfsTer10
This variant
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
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 · 4 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a frameshift deletion, NM_007294.4:c.4065_4068del, predicted to create p.(Asn1355LysfsTer10) / p.(N1355Kfs*10). It lies in BRCA1 exon 10(11), where the ENIGMA BRCA1 Table 4 assigns PVS1 for protein-truncating variants, and BRCA1 loss of function is an established disease mechanism in the official gene-specific framework.
Frameshift consequence p.(Asn1355LysfsTer10) / p.(N1355Kfs*10)Variant maps to BRCA1 exon 10(11)BRCA1 loss of function supported as disease mechanism
PM5
strong
Pathogenic
In the BRCA1 ENIGMA framework, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This frameshift lies in BRCA1 exon 10(11), and ENIGMA Table 4 assigns PM5_Strong (PTC) for truncating variants in this exon.
PM5 mode is PTC gene-specificnot classic same-residue missenseVariant maps to BRCA1 exon 10(11)
PP4
strong
Pathogenic
The BRCA1 clinical-history likelihood-ratio workbook contains this deletion as c.4065_4068delTCAA with 37 probands and LR 6590.9969. This exceeds the ENIGMA PP4 threshold for pathogenic clinical-history evidence and supports PP4.
Variant matched as c.4065_4068delTCAA in BRCA1 LR workbookN_Probands = 37LR = 6590.996910273256
Assessed · not applied
· 4 not met · 5 not assessed
Pathogenic
PS4
The variant has been reported in ClinVar and older literature sources, but no validated BRCA1 case-control analysis with odds ratio and confidence interval meeting the ENIGMA PS4 threshold was identified.
PM2
This variant is not absent from controls, so PM2 is not met.
PM3
No evidence was identified that this variant was observed with another BRCA1 pathogenic variant in a patient with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
Benign
BA1
BA1 is not met because the highest observed grpmax FAF is 2.93e-06 in gnomAD v2.1, which is well below the BRCA1 BA1 threshold of 0.001.
BS1
BS1 is not met because the highest observed grpmax FAF is 2.93e-06 in gnomAD v2.1, below both the BRCA1 BS1 supporting threshold of 0.00002 and strong threshold of 0.0001.
BS2
No evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the BRCA1 BS2 point-based framework, so BS2 was not assessed.
BS4
No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.
BP5
BP5 is not met because the available BRCA1 clinical-history likelihood ratio 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= 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.
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
strong
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