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.1 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 0.001.2 A calibrated functional study summarized by ENIGMA showed protein function similar to benign control variants for BRCA1 p.Asp411Glu, supporting BS3_Strong.3 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.4
Final classification
Benign
BS1BS3BP1BP6
BRCA1
c.1233T>G
p.Asp411Glu
This variant
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.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules
Classification rationale
BS1BS3BP1BP6
Benign
BRCA1 c.1233T>G
BS1 + BS3 + BP1 + BP6
→
Benign
3
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
4
cspec ↗spliceai ↗vcep_appendices_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 · 13 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
BS1
strong
Benign
This variant exceeds the ENIGMA BS1 threshold for benign population frequency. The grpmax FAF is 0.00024454 in gnomAD v2.1 and 0.00028752 in gnomAD v4.1, both above the BS1 threshold of 0.0001 in a non-founder population.
gnomAD v2.1: African/African American AF 0.000441165grpmax FAF 0.00024454.gnomAD v4.1: African/African American AF 0.000399574
BS3
strong
Benign
A calibrated functional study summarized by ENIGMA showed no damaging effect on protein function for this variant. ENIGMA Table 9 reports BRCA1 c.1233T>G (p.Asp411Glu) as BS3 Strong because one calibrated study found protein function similar to benign control variants.
ENIGMA Table 9 entry: BRCA1 c.1233T>G p.(Asp411Glu)BS3 Strongone calibrated study
BP1
strong
Benign
This missense variant is outside the BRCA1 clinically important domains used by ENIGMA and is not predicted to affect splicing. Asp411 lies outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, and SpliceAI shows a maximum delta score of 0.07, which is below the 0.1 threshold. This meets BP1_Strong.
Protein position 411 is outside ENIGMA-defined clinically important domains.SpliceAI max delta score 0.07 <= 0.1.
Assessed · not applied
· 4 not met · 9 not assessed
Pathogenic
PS1
No evidence was identified that this variant produces the same protein change or the same predicted splicing effect as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not applied.
PS3
Available functional evidence does not support a damaging effect.
PS4
No case-control study or other prevalence analysis was identified showing this variant is significantly enriched in affected individuals compared with controls, so PS4 was not applied.
PM2
This variant is not absent from population databases.
PM3
No evidence was identified that this variant has been observed with a second BRCA1 variant in a proband with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not applied.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not applied.
PP3
Available predictive evidence does not support a pathogenic computational call under the ENIGMA BRCA1 rules.
PP4
No qualifying multifactorial clinical-history likelihood ratio toward pathogenicity was identified for this variant.
Benign
BA1
The population frequency does not reach the ENIGMA BA1 threshold.
BS2
No qualifying evidence was identified showing this variant in enough individuals without features of BRCA1-related Fanconi anemia to reach the ENIGMA BS2 point thresholds, so BS2 was not applied.
BS4
No quantitative lack-of-segregation data were identified for this variant, so BS4 was not applied.
BP5
No qualifying multifactorial clinical-history likelihood ratio against pathogenicity was identified for this variant.
BP7
No RNA assay evidence was identified showing that this variant has no effect on mRNA splicing, so BP7 was not applied.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This 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.
v2.1
This 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.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0025%
· 41 / 1,614,214
0 hom · FAF 0.029%
0 hom · FAF 0.029%
African/African American 30 / 75,080 |
0.04% |
Remaining individuals 6 / 62,506 |
0.0096% |
Admixed American 4 / 60,014 |
0.0067% |
European (non-Finnish) 1 / 1,180,036 |
8.5e-05% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0043%
· 12 / 282,222
0 hom · FAF 0.024%
0 hom · FAF 0.024%
African/African American 11 / 24,934 |
0.044% |
Admixed American 1 / 35,410 |
0.0028% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Functional
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links