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LYFE SCIENCES
Project: HERA
NM_007294.4:c.4065_4068del
p.Asn1355LysfsTer10  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ cspec ↗
3

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.

PMID:31853058 ↗
4

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.

cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14).
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueN1355
Hotspots ↗