About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.3271C>G, p.(Pro1091Ala)
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
BP1Strong
BP1 · strong
This missense variant occurs at p.Pro1091Ala, outside the BRCA1 clinically important domains defined by ENIGMA (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP1 threshold of 0.1. These findings meet BP1_Strong.
Recorded classification: Uncertain significance
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official CSPEC/VCEP criteria-combination rules).
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
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 12 not assessed · 10 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.3271C>G (p.Pro1091Ala; p.P1091A) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, supporting rarity, although the ENIGMA BRCA1 PM2_Supporting rule was not applied because the required specified-control-set and coverage documentation were not identified here.
SpliceAI predicts no significant splice effect (maximum delta score 0.01, below the ENIGMA 0.1 and 0.2 splice thresholds); BayesDel no-AF is -0.072 and REVEL is 0.572, and because p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains, the ENIGMA BRCA1 missense rules support BP1_Strong and do not support PP3.
No criteria match.
Met · 1
BP1 StrongThis missense variant occurs at p.Pro1091Ala, outside the BRCA1 clinically important domains defined by ENIGMA (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP1 threshold of 0.1. These findings meet BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong applies to missense variants outside specified functional domains with SpliceAI ≤0.1.
Evidence considered
- Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.
- SpliceAI max delta = 0.01.
Sources
Not met · 5 · evaluated, threshold not reached
PVS1 This is a missense variant, not a nonsense, frameshift, initiation-codon, deletion, or canonical ±1,2 splice variant, so it does not meet the BRCA1 ENIGMA or generic null-variant requirements for PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 applies to qualifying loss-of-function variants or qualifying RNA evidence, not to this missense substitution.
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the ENIGMA framework.
- The variant-level PVS1 scaffold classifies this change outside the default null-variant buckets.
Sources
PP3 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA splicing threshold of 0.2 for PP3. BayesDel no-AF is -0.072, which is below the ENIGMA missense PP3 threshold of 0.28, and p.Pro1091Ala lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this missense rule. PP3 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for missense variants requires BayesDel ≥0.28 in a specified functional domain, or SpliceAI ≥0.2 for splicing impact.
Evidence considered
- SpliceAI max delta = 0.01.
- BayesDel no-AF = -0.0721595.
- REVEL = 0.572.
- Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BA1 filter allele frequency threshold of greater than 0.1% (FAF >0.001). Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires FAF >0.001.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the ENIGMA BS1 thresholds of greater than 0.002% or greater than 0.01% filter allele frequency. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 requires FAF above the specified benign thresholds.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and BayesDel no-AF is -0.072, which is below the ENIGMA benign missense threshold of 0.15. However, ENIGMA BRCA1 BP4 for missense variants is restricted to variants inside a clinically important functional domain, and p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this rule. BP4 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants requires BayesDel ≤0.15, SpliceAI ≤0.1, and location inside a specified functional domain.
Evidence considered
- SpliceAI max delta = 0.01.
- BayesDel no-AF = -0.0721595.
- REVEL = 0.572.
- Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.
Sources
Not assessed · 12 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed ClinVar or BRCA1 ENIGMA materials, so PS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS1 requires a previously classified pathogenic/likely pathogenic reference variant with the same protein or splicing consequence.
Evidence considered
- ClinVar search returned no result for this variant.
- No variant-specific PS1 lead was identified in the reviewed ENIGMA materials.
Still missing
- Direct expert-panel comparator evidence for the same amino acid change was not identified.
Sources
PS3 No variant-specific calibrated functional study assigning PS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, and no variant-specific reviewed functional evidence was identified in OncoKB. Details ▾Hide ▴
Rule
PS3 requires well-established functional evidence showing a damaging effect.
Evidence considered
- No c.3271C>G or p.Pro1091Ala entry was identified in the reviewed ENIGMA functional resources.
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Direct review of any newly published variant-specific functional studies would be needed if they exist.
Sources
PS4 No case-control dataset or other quantitative prevalence evidence showing enrichment of this variant in affected individuals versus controls was identified, so PS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires significant enrichment in affected individuals versus controls.
Evidence considered
- No usable ClinVar case-observation evidence was available.
- No variant-specific PS4-supporting dataset was identified in the reviewed materials.
Still missing
- Variant-specific case-control or aggregated affected-case prevalence data were not identified.
Sources
PM2 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which supports rarity; however, the ENIGMA BRCA1 PM2_Supporting rule specifically requires absence in the specified control datasets together with average read depth ≥25, and the required v3.1/depth documentation was not identified here, so PM2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2 is Supporting only when absence and coverage requirements are met.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Still missing
- The ENIGMA-specified gnomAD dataset/depth confirmation needed for PM2_Supporting was not documented.
Sources
PM3 No evidence was identified showing this variant in trans with another BRCA1 variant in an individual with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 is reserved for BRCA1/2-related Fanconi anemia observations.
Evidence considered
- No PM3-related proband evidence was identified in the reviewed materials.
Still missing
- No phase-confirmed recessive-disease observations were identified.
Sources
PP1 No quantitative co-segregation evidence was identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP1 requires quantitative segregation evidence.
Evidence considered
- No PP1-eligible family segregation dataset was identified.
Still missing
- No segregation likelihood-ratio data were identified.
Sources
PP4 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified in the reviewed BRCA1 clinical-history resources, so PP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 requires a calibrated multifactorial likelihood ratio ≥2.08.
Evidence considered
- No c.3271C>G entry was identified in the BRCA1 clinical-history LR workbook.
- No other quantitative PP4-supporting multifactorial LR was identified.
Still missing
- No variant-level clinical-history likelihood ratio entry was identified for this variant.
Sources
BS2 No proband-level evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based BS2 framework, so BS2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 requires point-based proband evidence.
Evidence considered
- No BS2-eligible recessive-disease exclusion data were identified.
Still missing
- No BS2 point-generating proband observations were identified.
Sources
BS3 No variant-specific calibrated functional study assigning BS3 was identified for this variant in the reviewed BRCA1 ENIGMA functional tables, so BS3 was not applied. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- No c.3271C>G or p.Pro1091Ala entry was identified in the reviewed ENIGMA functional resources.
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- Direct review of any newly published neutral functional studies would be needed if they exist.
Sources
BS4 No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- No BS4-eligible family segregation dataset was identified.
Still missing
- No segregation likelihood-ratio data against pathogenicity were identified.
Sources
BP5 No variant-specific multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds against pathogenicity was identified in the reviewed BRCA1 clinical-history resources, so BP5 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP5 requires a calibrated multifactorial likelihood ratio ≤0.48.
Evidence considered
- No c.3271C>G entry was identified in the BRCA1 clinical-history LR workbook.
- No other quantitative BP5-supporting multifactorial LR was identified.
Still missing
- No variant-level clinical-history likelihood ratio entry was identified for this variant.
Sources
BP7 This is a missense variant. ENIGMA BRCA1 BP7 for missense variants outside a clinically important domain requires mRNA evidence showing no damaging splice effect, and no such RNA study was identified for this variant, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7_Strong for missense variants requires mRNA evidence of no transcript abnormality.
Evidence considered
- SpliceAI max delta = 0.01.
- No variant-specific RNA assay entry was identified in the reviewed ENIGMA materials.
Still missing
- No variant-specific RNA study showing normal transcript profile was identified.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThe BRCA1 ENIGMA specification marks PS2 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PS2 as not applicable for this framework.
Sources
PM1 VCEPThe BRCA1 ENIGMA specification marks PM1 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PM1 as not applicable for BRCA1 ENIGMA v1.2.
Sources
PM4 VCEPThe BRCA1 ENIGMA specification marks PM4 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PM4 as not applicable.
Sources
PM5 N/AIn the BRCA1 ENIGMA specification, PM5 is repurposed for protein-truncating variants in eligible exons rather than classic same-residue missense logic. This missense variant is therefore not eligible for PM5. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 applies to qualifying PTC variants, not to this missense change.
Evidence considered
- PM5 candidate review marked the BRCA1 PM5 mode as PTC-specific.
- This variant is a missense substitution
- not a truncating variant.
Sources
PM6 VCEPThe BRCA1 ENIGMA specification marks PM6 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PM6 as not applicable.
Sources
PP2 VCEPThe BRCA1 ENIGMA specification marks PP2 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PP2 as not applicable.
Sources
PP5 VCEPThe BRCA1 ENIGMA specification marks PP5 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists PP5 as not applicable.
Sources
BP2 VCEPThe BRCA1 ENIGMA specification marks BP2 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists BP2 as not applicable.
Sources
BP3 VCEPThe BRCA1 ENIGMA specification marks BP3 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists BP3 as not applicable.
Sources
BP6 VCEPThe BRCA1 ENIGMA specification marks BP6 as not applicable. Details ▾Hide ▴
VCEP rule
Not applicable in ENIGMA BRCA1 v1.2.
Evidence considered
- CSPEC rule set lists BP6 as not applicable.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.3271C>G
- Protein (HGVS p.)
- NP_009225.1:p.(Pro1091Ala)
- GRCh38
- chr17:43092260 G>C
- GRCh37
- chr17:41244277 G>C
- ClinVar
- 3226136, 54934
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
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
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.572
- BayesDel
- -0.072
How the predictions were used
PP3 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, which is below the ENIGMA splicing threshold of 0.2 for PP3. BayesDel no-AF is -0.072, which is below the ENIGMA missense PP3 threshold of 0.28, and p.Pro1091Ala lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this missense rule. PP3 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for missense variants requires BayesDel ≥0.28 in a specified functional domain, or SpliceAI ≥0.2 for splicing impact.
Evidence considered
- SpliceAI max delta = 0.01.
- BayesDel no-AF = -0.0721595.
- REVEL = 0.572.
- Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.
Sources
BP4 SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, and BayesDel no-AF is -0.072, which is below the ENIGMA benign missense threshold of 0.15. However, ENIGMA BRCA1 BP4 for missense variants is restricted to variants inside a clinically important functional domain, and p.Pro1091Ala lies outside the BRCA1 RING, coiled-coil, and BRCT domains. REVEL 0.572 was reviewed, but ENIGMA BRCA1 uses BayesDel and domain context for this rule. BP4 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants requires BayesDel ≤0.15, SpliceAI ≤0.1, and location inside a specified functional domain.
Evidence considered
- SpliceAI max delta = 0.01.
- BayesDel no-AF = -0.0721595.
- REVEL = 0.572.
- Protein position 1091 is outside the ENIGMA BRCA1 clinically important domains.
Sources
BP7 This is a missense variant. ENIGMA BRCA1 BP7 for missense variants outside a clinically important domain requires mRNA evidence showing no damaging splice effect, and no such RNA study was identified for this variant, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7_Strong for missense variants requires mRNA evidence of no transcript abnormality.
Evidence considered
- SpliceAI max delta = 0.01.
- No variant-specific RNA assay entry was identified in the reviewed ENIGMA materials.
Still missing
- No variant-specific RNA study showing normal transcript profile was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.572. BayesDel score = -0.0721595.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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
Recorded maximum delta 0.010
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/?term=NM_007294.4%3Ac.3271C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41244277-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43092260-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43092260-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.3271…
- OncoKB ↗www.oncokb.org/gene/BRCA1/P1091A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.3271C%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
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.572. BayesDel score = -0.0721595.
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.