Starting

Initialising…

BRCA1

Final classification

Uncertain Significance

BRCA1 c.4211T>G · p.Leu1404Arg

BRCA1

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

Gene

BRCA1

Transcript

NM_007294.3

HGVS · transcript:coding

NM_007294.3:c.4211T>G

Consequence

N/A

GRCh38

chr17:43082550 A>C

GRCh37

chr17:41234567 A>C

Basis ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via CSPEC override). ▾

ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via CSPEC override).

Classification rationale

BP4 Uncertain Significance

BRCA1 c.4211T>G

The BRCA1 c.4211T>G (p.Leu1404Arg) variant has been reported in ClinVar, including an ENIGMA expert-panel classification of uncertain significance.¹ 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 v4.1.² 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.³

BP4 → Uncertain Significance

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_appendices_v1_2_2024_11_18bayesdelspliceai ↗revel

Gene diagram · NM_007294.3 · variants mapped to exon structure

BRCA1 NM_007294.3

Fetching transcript structure from UCSC…

Applied criteria · 1 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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= 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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

0.0004% · 1 / 251,348
0 hom

East Asian

1 / 18,386

0.0054%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

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 ↗

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 ↗

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.

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 ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots