About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.5561T>C, p.(Leu1854Pro)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
In calibrated BRCA1 functional studies summarized by the ENIGMA expert panel, c.5561T>C (p.Leu1854Pro) showed damaging loss-of-function behavior similar to pathogenic control variants in two studies, supporting PS3_Strong.
PP3Supporting
PP3 · supporting
This missense variant lies in the BRCA1 BRCT repeat domain, where ENIGMA allows PP3 for variants with predicted protein impact. BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI shows no predicted splice effect (max delta score 0.00), supporting a deleterious protein effect and meeting PP3_Supporting.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Official ClinGen ENIGMA BRCA1/BRCA2 specification v1.2 final-classification framework using Table 3 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.
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.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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: 3 met · 6 not met · 8 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.5561T>C (p.Leu1854Pro) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classifies it as likely pathogenic.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
In calibrated BRCA1 functional studies summarized by ENIGMA, this variant showed damaging loss-of-function behavior consistent with pathogenic control variants in two studies, supporting PS3_Strong.
This missense change lies in the BRCA1 BRCT repeat domain; BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI predicts no significant splice impact with a max delta score of 0.00, supporting a deleterious protein effect rather than a splicing effect.
No criteria match.
Met · 3
PS3 StrongIn calibrated BRCA1 functional studies summarized by the ENIGMA expert panel, c.5561T>C (p.Leu1854Pro) showed damaging loss-of-function behavior similar to pathogenic control variants in two studies, supporting PS3_Strong. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: PS3 Strong for c.5561T>C
- Findlay 2018 reported LOF
- Fernandes 2019 reported pathogenic/damaging effect
Sources
PP3 SupportingThis missense variant lies in the BRCA1 BRCT repeat domain, where ENIGMA allows PP3 for variants with predicted protein impact. BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI shows no predicted splice effect (max delta score 0.00), supporting a deleterious protein effect and meeting PP3_Supporting. Details ▾Hide ▴
Evidence considered
- BRCT domain aa 1650-1857
- BayesDel no-AF 0.406711 (>0.28 threshold)
- REVEL 0.731
- SpliceAI max delta score 0.00
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No previously classified pathogenic variant producing the same amino acid substitution was identified, so PS1 is not met. Details ▾Hide ▴
Evidence considered
- Variant consequence p.(Leu1854Pro)
Still missing
- A comprehensive same-amino-acid comparison set was not identified in the reviewed materials.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold FAF >0.001
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or greater than 0.01%. BS1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 thresholds FAF >0.00002 or >0.0001
Sources
BS3 Available calibrated functional evidence does not show retained normal BRCA1 function for this variant. Instead, ENIGMA Table 9 summarizes damaging loss-of-function results in two studies, so BS3 is not met. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong
- not BS3
- Findlay 2018 LOF
- Fernandes 2019 pathogenic/damaging effect
Sources
BP1 This missense variant is located in the BRCA1 BRCT functional domain rather than outside a clinically important domain, so the ENIGMA BP1_Strong rule is not met. Details ▾Hide ▴
Evidence considered
- BRCT domain aa 1650-1857
- Variant p.(Leu1854Pro) is within BRCT
- SpliceAI max delta score 0.00
Sources
BP4 ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF at or below 0.15 and SpliceAI at or below 0.1. Although SpliceAI is 0.00, BayesDel is 0.406711, which is above the benign threshold and instead supports PP3, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF 0.406711
- BP4 benign threshold ≤0.15
- SpliceAI max delta score 0.00
Sources
Not assessed · 8 · no assessment recorded
PS4 No case-control study or other quantitative evidence showing that this variant is significantly enriched in affected individuals versus controls was identified, so PS4 was not assessed. Details ▾Hide ▴
Still missing
- No odds ratio or confidence interval was identified for this exact variant.
- No affected-case versus control count set was identified for this exact variant.
PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity. However, ENIGMA PM2_Supporting requires absence in the specified population datasets with adequate coverage, and the full rule elements needed for formal PM2 assignment were not identified here, so PM2 was not assessed. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Still missing
- A direct gnomAD v3.1 non-cancer review was not identified in the reviewed materials.
- Average read depth information required for formal ENIGMA PM2 application was not identified.
Sources
PM3 No evidence was identified that this variant occurred with another BRCA1 pathogenic variant in a patient with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
PP1 No quantitative segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Still missing
- No pedigree-level likelihood ratio identified.
- No meiosis count or segregation analysis identified.
PP4 No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this exact variant, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
- Reviewed BRCA1 clinical-history LR resource without exact variant hit
Still missing
- Exact variant was not identified in the reviewed BRCA1 clinical-history LR table.
- No combined LR ≥2.08 was identified for this exact variant.
Sources
BS2 No evidence was identified from unaffected individuals or from BRCA1-related recessive disease point scoring to support BS2, so this criterion was not assessed. Details ▾Hide ▴
Still missing
- No unaffected adult carrier data identified.
- No BRCA1 recessive disease point totals identified.
Sources
BS4 No quantitative non-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Still missing
- No family-level likelihood ratio ≤0.48 identified.
- No discordant segregation evidence identified.
BP5 No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this exact variant, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- Reviewed BRCA1 clinical-history LR resource without exact variant hit
Still missing
- Exact variant was not identified in the reviewed BRCA1 clinical-history LR table.
- No combined LR ≤0.48 was identified for this exact variant.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, initiation-loss, or canonical ±1/2 splice variant, and SpliceAI predicts no splice effect (max delta score 0.00). Available evidence does not support applying PVS1 for this change. Details ▾Hide ▴
Evidence considered
- Missense change p.(Leu1854Pro)
- Generic PVS1 scaffold: not in default null-variant bucket
- SpliceAI max delta score 0.00
Sources
PS2 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
PM1 N/AAlthough this variant lies in the BRCA1 BRCT region, PM1 is not applicable in the BRCA1 ENIGMA specification, which handles domain information through other criteria. Details ▾Hide ▴
Evidence considered
- BRCT domain defined as aa 1650-1857
- ENIGMA BRCA1 v1.2 marks PM1 not applicable
Sources
PM4 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
PM5 N/AIn the BRCA1 ENIGMA specification, PM5 is used for protein-termination variants in exons with prior proven pathogenic protein-termination variants. This variant is missense, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is missense p.(Leu1854Pro)
- ENIGMA PM5 rule is framed for PTC variants
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
PP2 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
BP2 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
BP3 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
BP6 N/AThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
BP7 N/AThis is a missense variant in the BRCA1 BRCT functional domain, and no RNA study showing a normal transcript effect was identified. The ENIGMA BP7 rules are not met for this variant. Details ▾Hide ▴
Evidence considered
- Missense variant in BRCT domain
- SpliceAI max delta score 0.00
- No variant-specific normal RNA assay identified
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.5561T>C
- Protein (HGVS p.)
- NP_009225.1:p.(Leu1854Pro)
- GRCh38
- chr17:43045709 A>G
- GRCh37
- chr17:41197726 A>G
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
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis missense variant lies in the BRCA1 BRCT repeat domain, where ENIGMA allows PP3 for variants with predicted protein impact. BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI shows no predicted splice effect (max delta score 0.00), supporting a deleterious protein effect and meeting PP3_Supporting. Details ▾Hide ▴
Evidence considered
- BRCT domain aa 1650-1857
- BayesDel no-AF 0.406711 (>0.28 threshold)
- REVEL 0.731
- SpliceAI max delta score 0.00
Sources
BP4 ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF at or below 0.15 and SpliceAI at or below 0.1. Although SpliceAI is 0.00, BayesDel is 0.406711, which is above the benign threshold and instead supports PP3, so BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF 0.406711
- BP4 benign threshold ≤0.15
- SpliceAI max delta score 0.00
Sources
BP7 N/AThis is a missense variant in the BRCA1 BRCT functional domain, and no RNA study showing a normal transcript effect was identified. The ENIGMA BP7 rules are not met for this variant. Details ▾Hide ▴
Evidence considered
- Missense variant in BRCT domain
- SpliceAI max delta score 0.00
- No variant-specific normal RNA assay identified
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.731. BayesDel score = 0.406711.
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/55631/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41197726-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43045709-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.5561…
- OncoKB ↗www.oncokb.org/gene/BRCA1/L1854P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.5561T%3EC
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely pathogenic (3 clinical laboratories) and as Likely Pathogenic 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 = 0.00). REVEL score = 0.731. BayesDel score = 0.406711.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.