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

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_007294.3 · variants mapped to exon structure

BRCA1 NM_007294.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

This missense variant lies in the BRCA1 coiled-coil domain (aa 1391-1424). BayesDel no-AF is 0.094842, which is below the BRCA1 BP4 threshold of ≤0.15, and SpliceAI max delta score is 0.02, which is below the ≤0.1 splice threshold. These findings support BP4_Supporting under the ENIGMA BRCA1 rule. REVEL is 0.331 and does not change the VCEP rule assignment.

Protein position 1404 lies within coiled-coil domain aa 1391-1424BayesDel no-AF 0.094842SpliceAI max delta 0.02

cspec ↗spliceai ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS1 No previously classified variant causing the same amino acid change was identified in the reviewed BRCA1 materials, so PS1 could not be established from the available evidence.

PS3 No variant-specific damaging functional result for c.4211T>G (p.Leu1404Arg) was identified in the reviewed ENIGMA BRCA1 curated functional tables, so PS3 is not established from the available evidence.

PS4 This variant has been reported in ClinVar, but no case-control evidence showing significant enrichment in affected individuals at the ENIGMA BRCA1 PS4 threshold was identified.

PM2 This variant is not absent from controls because it is present once in gnomAD v2.1 (1/251348 alleles; AF 3.97855e-06; highest observed East Asian AF 5.43892e-05), even though it is absent from gnomAD v4.1.

PM3 No evidence was identified that this variant occurred with a second BRCA1 variant in a person with BRCA1-related Fanconi anemia, so PM3 could not be assessed.

PP1 No quantitative co-segregation evidence for this exact variant was identified, so PP1 could not be assessed.

PP3 Available computational evidence does not support PP3 under the ENIGMA BRCA1 rule.

PP4 No variant-specific clinical-history likelihood ratio was identified for this exact BRCA1 variant in the reviewed clinical-history resource, so PP4 could not be assigned.

Benign

BA1 Population data do not meet BA1.

BS1 Population data do not meet BS1.

BS2 No evidence was identified showing this variant in individuals meeting the BRCA1 BS2 framework for absence of Fanconi anemia features, so BS2 could not be assessed.

BS3 No variant-specific benign functional result for c.4211T>G (p.Leu1404Arg) was identified in the reviewed ENIGMA BRCA1 curated functional tables, so BS3 is not established from the available evidence.

BS4 No quantitative lack-of-segregation evidence for this exact variant was identified, so BS4 could not be assessed.

BP1 This missense variant is in the BRCA1 coiled-coil domain (aa 1391-1424), which is a clinically important functional domain in the ENIGMA BRCA1 specification, so it does not meet BP1_Strong for variants outside such domains.

BP5 No variant-specific clinical-history likelihood ratio in the benign direction was identified for this exact BRCA1 variant in the reviewed clinical-history resource, so BP5 could not be assigned.

BP7 No RNA study showing no transcript effect was identified for this variant.

N/A · 11 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6

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

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