NM_007294.3:c.1233T>G (p.Asp411Glu) is a missense variant in BRCA1 exon 10, classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 41804).1 This variant is present in gnomAD v2.1 at 12/282,222 alleles (AF=4.25e-05) with a grpmax filter allele frequency of 0.024% (0.00024454) in the African/African American subpopulation (11/24,934 alleles), exceeding the ENIGMA BS1_Strong threshold of >0.01%.2 ENIGMA Table 9 (v1.2.0) assigns BS3_Strong to this variant based on calibrated functional assay evidence from Bouwman et al. 2020 (PMID:32546644), demonstrating protein function in homologous recombination repair complementation similar to benign control variants.3 Codon 411 is located outside all three (potentially) clinically important functional domains defined by ENIGMA for BRCA1: RING finger (aa 2-101), coiled-coil (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI predicts no splicing impact (max delta score 0.07). These findings satisfy ENIGMA BP1_Strong criteria.4 Parsons et al. 2019 multifactorial likelihood analysis (PMID:31131967) reports a combined LR of 1.29, a segregation LR of 1.93, and a family history LR of 6.48 for this variant. The combined LR is in the neutral range and does not independently support either pathogenic (PP4) or benign (BP5) classification.5 No evidence was found to support any pathogenic criterion. PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM2, PM5, PM6, PP1, PP2, PP3, PP4, and PP5 are all either not met or not applicable.6 Under the ENIGMA Table 3 combination rules, two or more Strong Benign criteria support a Benign classification. The three Strong Benign criteria met (BS1_Strong, BS3_Strong, BP1_Strong) satisfy the Benign classification threshold.7
BRCA1
Final classification
Unclassified
BRCA1 c.1233T>G · p.Asp411Glu
BRCA1
NM_007294.3:c.1233T>G (p.Asp411Glu) is a missense variant in BRCA1 exon 10, classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel (ClinVar Variation ID: 41804).
Classification rationale
BS1BS3BP1BP6
Unclassified
BRCA1 c.1233T>G
BS1 + BS3 + BP1 + BP6
→
Unclassified
3
vcep_specifications_table9_v1_2_2024_11_18
5
vcep_humu_40_1557_s001
6
gnomad_v2 ↗gnomad_v4 ↗cspec ↗spliceai ↗bayesdel
7
cspec ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 12 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
ENIGMA BS1_Strong applies when FAF exceeds 0.01% (FAF > 0.0001). gnomAD v2.1 grpmax FAF is 0.00024454 (0.024%); the variant is observed in 12/282,222 total alleles (AF=4.25e-05) with highest subpopulation frequency in the African/African American population (11/24,934 alleles, AF=0.044%). This exceeds the ENIGMA BS1_Strong threshold of >0.01%.
gnomAD v2.1: grpmax FAF=0.00024454 (0.024%) > ENIGMA BS1_Strong threshold of 0.01%. 12 total alleles11 in AFR subpopulation.
✓
BS3
strong
Benign
ENIGMA Table 9 (v1.2.0) explicitly assigns BS3_Strong for NM_007294.3:c.1233T>G (p.Asp411Glu). One calibrated functional study (Bouwman et al. 2020, PMID:32546644) demonstrates that this variant exhibits protein function similar to benign control variants in homologous recombination repair complementation assays, meeting the criteria for well-established functional evidence of no damaging effect.
ENIGMA Table 9: BS3_Strong assignedBouwman 2020 functional assay shows no damaging effect on protein function in HR complementation.
✓
BP1
strong
Benign
ENIGMA BP1_Strong applies to missense variants located outside all (potentially) clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). Codon 411 is outside the three defined domains: RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857). SpliceAI max delta score is 0.07 (≤0.1). Both conditions for BP1_Strong are satisfied.
Position 411 outside all three clinically important functional domains (RING 2-101coiled-coil 1391-1424BRCT 1650-1857)
Assessed · not applied
Pathogenic
PS1
No previously classified pathogenic or likely pathogenic missense variant at codon 411 with the same amino acid change (p.Asp411Glu) was identified.
PS3
ENIGMA Table 9 (v1.2.0) assigns BS3_Strong for this variant, not PS3.
PS4
No case-control study has demonstrated significantly increased prevalence of this variant in affected individuals (p≤0.05, OR≥4).
PM2
ENIGMA PM2_Supporting requires absence from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer).
PP1
No co-segregation data demonstrating segregation of this variant with disease in multiple affected family members was identified.
PP3
ENIGMA PP3 requires either (a) missense variant inside a clinically important functional domain with BayesDel no-AF score ≥0.28, or (b) SpliceAI delta score ≥0.2.
PP4
ENIGMA PP4 uses multifactorial combined likelihood ratio toward pathogenicity.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer).
BS2
ENIGMA BS2 requires proband-level data demonstrating observation in a healthy adult in the absence of Fanconi Anemia phenotype.
BS4
ENIGMA BS4 requires a segregation LR ≤0.48 (Supporting) or lower for stronger evidence levels.
BP5
ENIGMA BP5 uses multifactorial combined likelihood ratio against pathogenicity.
BP7
ENIGMA BP7_Strong(RNA) requires well-established mRNA transcript assay evidence showing no damaging effect on splicing for missense variants outside clinically important functional domains.
N/A · 9
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP4
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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). (ClinVarID = 41804)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.639. BayesDel score = -0.196447.
Functional
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.
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.
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. 9 further PMIDs triaged but not cited — see Sources & References.
Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
15235020 ↗
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
CLINVAR
15385441 ↗
Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.
CLINVAR
16267036 ↗
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
CLINVAR
16518693 ↗
Natural selection and mammalian BRCA1 sequences: elucidating functionally important sites relevant to breast cancer susceptibility in humans.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR