Back
LYFE SCIENCES
Project: HERA
NM_007294.3:c.4211T>G
p.Leu1404Arg  ·  BRCA1
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The BRCA1 c.4211T>G (p.Leu1404Arg) variant has been reported in ClinVar, including an ENIGMA expert-panel classification of uncertain significance.

clinvar ↗
2

This variant is very rare in population databases, with 1 of 251348 alleles in gnomAD v2.1 (AF 3.97855e-06; highest observed East Asian AF 5.43892e-05) and no observation in gnomAD v4.1.

gnomad_v2 ↗ gnomad_v4 ↗
3

In silico evidence supports a benign computational interpretation under the ENIGMA BRCA1 framework because the variant is in the coiled-coil domain, BayesDel no-AF is 0.094842 (BP4 threshold ≤0.15), and SpliceAI max delta score is 0.02 (BP4 threshold ≤0.1); REVEL is 0.331 but does not alter the VCEP rule assignment.

cspec ↗ spliceai ↗
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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
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= 3.97855e-06; MAF= 0.00040%, 1/251348 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.43892e-05; MAF= 0.00544%, 1/18386 alleles, homozygotes = 0).
gnomAD v4.1Absent from gnomAD v4.1.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.331. BayesDel score = 0.094842.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL1404
Hotspots ↗