About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.4211T>G, p.(Leu1404Arg)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA1 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules via CSPEC override).
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD 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).
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BRCA1 c.4211T>G (p.Leu1404Arg) variant has been reported in ClinVar, including an ENIGMA expert-panel classification of uncertain significance.
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.
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.
No criteria match.
Met · 1
BP4 SupportingThis 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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4_Supporting
Evidence considered
- Protein position 1404 lies within coiled-coil domain aa 1391-1424
- BayesDel no-AF 0.094842
- SpliceAI max delta 0.02
- REVEL 0.331
Sources
Not met · 5 · evaluated, threshold not reached
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. The ENIGMA BRCA1 PM2 rule requires absence from controls, so PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM2_Supporting
Evidence considered
- gnomAD v2.1 total AC 1/AN 251348
- gnomAD v4.1 absent
Sources
PP3 Available computational evidence does not support PP3 under the ENIGMA BRCA1 rule. BayesDel no-AF is 0.094842, which is below the PP3 threshold of ≥0.28, and SpliceAI max delta score is 0.02, which is below the splice threshold of ≥0.2. REVEL is 0.331, but ENIGMA BRCA1 uses BayesDel and SpliceAI for this rule. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3
Evidence considered
- BayesDel no-AF 0.094842
- SpliceAI max delta 0.02
- REVEL 0.331
Sources
BA1 Population data do not meet BA1. The variant was seen once in gnomAD v2.1 and was absent from gnomAD v4.1, and no non-founder population frequency above the BRCA1 BA1 threshold was identified. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BA1
Evidence considered
- gnomAD v2.1 total AC 1/AN 251348
- gnomAD v4.1 absent
Sources
BS1 Population data do not meet BS1. The variant is very rare in gnomAD v2.1 and absent from gnomAD v4.1, and no non-founder population filter allele frequency above the BRCA1 BS1 thresholds was identified. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS1
Evidence considered
- gnomAD v2.1 total AC 1/AN 251348
- gnomAD v4.1 absent
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP1_Strong
Evidence considered
- Protein position 1404 lies within coiled-coil domain aa 1391-1424
- SpliceAI max delta 0.02
Sources
Not assessed · 11 · no assessment recorded
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS1
Evidence considered
- Reviewed under ENIGMA BRCA1 PS1 framework
Still missing
- A direct same-amino-acid pathogenic/likely pathogenic comparison variant was not identified in the reviewed sources.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS3
Evidence considered
- No exact variant-specific calibrated functional entry identified in reviewed BRCA1 VCEP tables
Still missing
- No exact c.4211T>G row was identified in ENIGMA Table 9 or the supplementary functional dataset.
- Direct review of any additional primary functional literature would be needed if PS3 remains clinically important.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
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. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM3
Evidence considered
- Reviewed under BRCA1 PM3 Fanconi anemia framework
Still missing
- No recessive-disease proband data were identified.
Sources
PP1 No quantitative co-segregation evidence for this exact variant was identified, so PP1 could not be assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP1
Evidence considered
- No exact variant match identified in reviewed multifactorial workbook
Still missing
- No pedigree-based likelihood ratio for this exact variant was identified.
Sources
cspec ↗vcep_humu_40_1557_s001
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP4
Evidence considered
- No exact variant match identified in reviewed BRCA1 clinical-history LR workbook
Still missing
- No exact HGVS match was identified in the BRCA1 clinical-history LR workbook.
- A variant-specific LR of at least 2.08 would be required for PP4_Supporting.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS2
Evidence considered
- Reviewed under BRCA1 BS2 framework
Still missing
- No BS2 point-based proband data were identified.
Sources
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS3
Evidence considered
- No exact variant-specific calibrated benign functional entry identified in reviewed BRCA1 VCEP tables
Still missing
- No exact c.4211T>G row was identified in ENIGMA Table 9 or the supplementary functional dataset.
- Direct review of additional primary functional literature would be needed if BS3 remains clinically important.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation evidence for this exact variant was identified, so BS4 could not be assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS4
Evidence considered
- No exact variant match identified in reviewed multifactorial workbook
Still missing
- No family-based likelihood ratio showing non-segregation for this exact variant was identified.
Sources
cspec ↗vcep_humu_40_1557_s001
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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP5
Evidence considered
- No exact variant match identified in reviewed BRCA1 clinical-history LR workbook
Still missing
- No exact HGVS match was identified in the BRCA1 clinical-history LR workbook.
- A variant-specific LR of 0.48 or lower would be required for BP5_Supporting.
Sources
BP7 No RNA study showing no transcript effect was identified for this variant. SpliceAI predicts little splice effect (max delta score 0.02), but BP7 in this framework requires the variant-type and study conditions described by the BRCA1 specification, so BP7 is not established from the available evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7
Evidence considered
- SpliceAI max delta 0.02
- No variant-specific RNA assay identified
Still missing
- No variant-specific RNA assay result was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Leu1404Arg), and does not fall into the BRCA1 loss-of-function categories used for PVS1 such as nonsense, frameshift, or canonical ±1,2 splice variants. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PVS1 / generic PVS1 scaffold
Evidence considered
- Protein consequence is missense p.(Leu1404Arg)
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PS2 N/AThis BRCA1 specification marks PS2 as not applicable for this framework. Details ▾Hide ▴
PM1 N/AThis BRCA1 specification marks PM1 as not applicable in this framework. Details ▾Hide ▴
PM4 N/AThis BRCA1 specification marks PM4 as not applicable in this framework. Details ▾Hide ▴
PM5 N/AIn this BRCA1 specification, PM5 is used for protein-truncating variants with a premature termination codon in eligible exons. This variant is missense, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM5_PTC
Evidence considered
- Variant is missense rather than PTC-generating
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis BRCA1 specification marks PM6 as not applicable for this framework. Details ▾Hide ▴
PP2 N/AThis BRCA1 specification marks PP2 as not applicable in this framework. Details ▾Hide ▴
PP5 N/AThis BRCA1 specification marks PP5 as not applicable in this framework. Details ▾Hide ▴
BP2 N/AThis BRCA1 specification marks BP2 as not applicable in this framework. Details ▾Hide ▴
BP3 N/AThis BRCA1 specification marks BP3 as not applicable in this framework. Details ▾Hide ▴
BP6 N/AThis BRCA1 specification marks BP6 as not applicable in this framework. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.4211T>G
- Protein (HGVS p.)
- NP_009225.1:p.(Leu1404Arg)
- GRCh38
- chr17:43082550 A>C
- GRCh37
- chr17:41234567 A>C
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.3. Select a row to find it on the plot.
BRCA1NM_007294.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
1 / 251,348 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v2.1
AF 4e-06 · 1 / 251,348 alleles · 0 hom
| East Asian1 / 18,386 | 5.4e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD 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).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis 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. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4_Supporting
Evidence considered
- Protein position 1404 lies within coiled-coil domain aa 1391-1424
- BayesDel no-AF 0.094842
- SpliceAI max delta 0.02
- REVEL 0.331
Sources
PP3 Available computational evidence does not support PP3 under the ENIGMA BRCA1 rule. BayesDel no-AF is 0.094842, which is below the PP3 threshold of ≥0.28, and SpliceAI max delta score is 0.02, which is below the splice threshold of ≥0.2. REVEL is 0.331, but ENIGMA BRCA1 uses BayesDel and SpliceAI for this rule. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3
Evidence considered
- BayesDel no-AF 0.094842
- SpliceAI max delta 0.02
- REVEL 0.331
Sources
BP7 No RNA study showing no transcript effect was identified for this variant. SpliceAI predicts little splice effect (max delta score 0.02), but BP7 in this framework requires the variant-type and study conditions described by the BRCA1 specification, so BP7 is not established from the available evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7
Evidence considered
- SpliceAI max delta 0.02
- No variant-specific RNA assay identified
Still missing
- No variant-specific RNA assay result was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.331. BayesDel score = 0.094842.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/491071/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41234567-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43082550-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.4211…
- OncoKB ↗www.oncokb.org/gene/BRCA1/L1404R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.4211T%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD 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).
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.331. BayesDel score = 0.094842.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.