Classification rationale

BS1BS3BP1BP6 Benign

BRCA1 c.1233T>G

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

BS1 + BS3 + BP1 + BP6 → Benign

1 clinvar ↗

2 cspec ↗gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_specifications_table9_v1_2_2024_11_18

4 cspec ↗spliceai ↗vcep_appendices_v1_2_2024_11_18

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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%

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 v4 ↗ gnomAD v2 ↗

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 ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

6papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

PMID cspec

PMID cspec ↗

Found