Back
LYFE SCIENCES
Project: HERA
NM_007294.4:c.1233T>G
p.Asp411Glu  ·  BRCA1
Starting
Initialising…
0%
Legacy Engine
Processing…
Classification rationale
1

The BRCA1 c.1233T>G (p.Asp411Glu; p.D411E) variant has not been reported in COSMIC and has been reported in ClinVar, including a Benign expert-panel classification from ClinGen ENIGMA.

clinvar ↗
2

This variant is present in population databases, with gnomAD grpmax FAF values of 0.00024454 in v2.1 and 0.00028752 in v4.1, both above the ENIGMA BS1 threshold of 0.0001 and below the BA1 threshold of 0.001.

cspec ↗ gnomad_v2 ↗ gnomad_v4 ↗
3

A calibrated functional study summarized by ENIGMA showed protein function similar to benign control variants for BRCA1 p.Asp411Glu, supporting BS3_Strong.

cspec ↗
4

Asp411Glu lies outside the BRCA1 RING, coiled-coil, and BRCT domains, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.07, which is below the 0.1 threshold used for BP1_Strong.

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= 4.25197e-05; MAF= 0.00425%, 12/282222 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000441165; MAF= 0.04412%, 11/24934 alleles, homozygotes = 0); grpmax FAF= 0.00024454.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.53994e-05; MAF= 0.00254%, 41/1614214 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000399574; MAF= 0.03996%, 30/75080 alleles, homozygotes = 0); grpmax FAF= 0.00028752.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 = 0.07).
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.
ResidueD411
Hotspots ↗