About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.5140G>T, p.(Val1714Phe)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
In a calibrated functional study, this variant showed loss of function/complete functional impact relative to wild type, and ENIGMA BRCA1 Table 9 assigns PS3 at strong strength for c.5140G>T (p.Val1714Phe). This supports a damaging effect on BRCA1 protein function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the ENIGMA BRCA1 specification, absence from controls supports PM2 at supporting strength.
PP3Supporting
PP3 · supporting
This missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain (aa 1650-1857). BayesDel no-AF is 0.482282, which is above the ENIGMA PP3 threshold of 0.28 for damaging protein effect, REVEL is 0.812, and SpliceAI is low at 0.09; together these data support a damaging protein effect rather than a splice-mediated explanation.
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
ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 criteria-combination rules (CSPEC/VCEP 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
Absent from gnomAD v2.1.
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 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.
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: 4 met · 7 not met · 8 not assessed · 9 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.5140G>T (p.Val1714Phe) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the overall classification is Likely Pathogenic with expert panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
In a calibrated BRCA1 functional study, this variant showed complete functional impact consistent with loss of function, and ENIGMA assigns PS3_Strong for this variant.
Computational data support a damaging protein effect because the variant is in the BRCT repeats, BayesDel no-AF is 0.482282, and REVEL is 0.812, while SpliceAI predicts no significant splice effect with a max delta score of 0.09.
No criteria match.
Met · 4
PS3 StrongIn a calibrated functional study, this variant showed loss of function/complete functional impact relative to wild type, and ENIGMA BRCA1 Table 9 assigns PS3 at strong strength for c.5140G>T (p.Val1714Phe). This supports a damaging effect on BRCA1 protein function. Details ▾Hide ▴
Rule
ENIGMA Table 9 assigns PS3_Strong when calibrated functional data support a damaging effect.
Evidence considered
- ENIGMA Table 9 row: PS3 Strong for c.5140G>T
- Supplementary Table 4: Functional impact - complete / LOF
- Findlay saturation genome editing data
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the ENIGMA BRCA1 specification, absence from controls supports PM2 at supporting strength. Details ▾Hide ▴
Rule
ENIGMA applies PM2_Supporting when a variant is absent from controls in the specified gnomAD datasets.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP3 SupportingThis missense variant lies within the BRCA1 BRCT repeats, a clinically important functional domain (aa 1650-1857). BayesDel no-AF is 0.482282, which is above the ENIGMA PP3 threshold of 0.28 for damaging protein effect, REVEL is 0.812, and SpliceAI is low at 0.09; together these data support a damaging protein effect rather than a splice-mediated explanation. Details ▾Hide ▴
Rule
ENIGMA applies PP3 for missense variants in a clinically important domain with BayesDel no-AF ≥0.28, or for predicted splice impact with SpliceAI ≥0.2.
Evidence considered
- BRCT domain location
- BayesDel no-AF 0.482282
- REVEL 0.812
- SpliceAI max delta 0.09
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PVS1 This variant is a missense substitution and does not fall into the BRCA1 null-variant categories used for PVS1. The generic PVS1 scaffold does not place it in a nonsense, frameshift, or canonical ±1,2 splice bucket, and SpliceAI predicts no significant splice effect (max delta score 0.09), so a null mechanism is not supported. Details ▾Hide ▴
Rule
ENIGMA/ClinGen BRCA1 PVS1 is reserved for null variants or qualifying RNA-null evidence; this variant does not meet those conditions.
Evidence considered
- Missense change p.(Val1714Phe)
- Generic PVS1 scaffold: not a default null-variant bucket
- SpliceAI max delta 0.09
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is far below the ENIGMA BA1 stand-alone threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
BA1 requires filter allele frequency >0.1% in the specified gnomAD datasets.
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 does not meet the ENIGMA BS1 population thresholds of filter allele frequency greater than 0.002% or greater than 0.01%. Details ▾Hide ▴
Rule
BS1 requires filter allele frequency above the ENIGMA BS1 thresholds in the specified gnomAD datasets.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS3 Available functional evidence does not show no damaging effect. Instead, calibrated BRCA1 functional data support loss of function for this variant, and ENIGMA assigns PS3_Strong rather than BS3. Details ▾Hide ▴
Rule
BS3 requires well-established studies showing no damaging effect on protein function.
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong
- Supplementary Table 4: complete functional impact / LOF
Sources
BP1 BP1_Strong applies to missense variants outside the BRCA1 clinically important domains with no predicted splice effect. This variant is p.(Val1714Phe) within the BRCT repeats (aa 1650-1857), so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BP1_Strong requires a missense or similar variant outside a clinically important functional domain and no splicing predicted.
Evidence considered
- Variant is within BRCT repeats
- SpliceAI max delta 0.09
Sources
BP4 For a BRCA1 missense variant in a clinically important domain, BP4 requires BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower. Although SpliceAI is low at 0.09, BayesDel is 0.482282 and REVEL is 0.812, so computational evidence does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BP4 for missense variants in functional domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.482282
- REVEL 0.812
- SpliceAI max delta 0.09
Sources
BP7 BP7 in this framework requires qualifying RNA evidence and/or variant-type conditions that are not met here. This is a missense variant within the BRCA1 BRCT functional domain, SpliceAI is low at 0.09, and no RNA assay showing no transcript effect was identified, so BP7 was not applied. Details ▾Hide ▴
Rule
For BRCA1, BP7 use depends on variant type, domain context, and in some settings RNA evidence showing no damaging transcript effect.
Evidence considered
- Missense variant in BRCT domain
- SpliceAI max delta 0.09
- No RNA assay identified
Still missing
- A qualifying RNA study showing no damaging transcript effect would be needed to support BP7 in this context.
Sources
Not assessed · 8 · no assessment recorded
PS1 No qualifying previously classified pathogenic or likely pathogenic reference variant with the same amino acid change or the same predicted splicing effect was identified in the reviewed sources, so PS1 was not applied. Details ▾Hide ▴
Rule
PS1 requires a previously classified pathogenic/likely pathogenic variant causing the same protein change or the same predicted splice effect.
Evidence considered
- PS1 rule reviewed under ENIGMA BRCA1 specification
Still missing
- A targeted same-amino-acid and same-splice-effect reference-variant search would be needed to fully exclude PS1.
Sources
PS4 No case-control study or exact affected-versus-control enrichment data demonstrating significant overrepresentation of this variant were identified, so PS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- ClinVar reporting reviewed
- No case-control enrichment data identified
Still missing
- Variant-specific case-control evidence with odds ratio and confidence interval would be needed for PS4.
Sources
PM3 No evidence was identified that this variant was observed with a second BRCA1 pathogenic variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not applied. Details ▾Hide ▴
Rule
ENIGMA PM3 is limited to BRCA1/2-related Fanconi anemia contexts with point-based scoring.
Evidence considered
- No qualifying PM3 evidence identified
Still missing
- Fanconi anemia phenotype and phase-confirmed biallelic observations would be needed for PM3.
Sources
PP1 No quantitative co-segregation data for this variant were identified, so PP1 was not applied. Details ▾Hide ▴
Rule
ENIGMA PP1 requires quantitative co-segregation evidence with LR-based strength assignment.
Evidence considered
- No qualifying segregation LR identified
Still missing
- Family-level segregation data with likelihood-ratio calculation would be needed for PP1.
Sources
cspec ↗vcep_humu_40_1557_s001
PP4 No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so PP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA PP4 requires a multifactorial clinical-data LR of at least 2.08, with higher thresholds for stronger weights.
Evidence considered
- BRCA1 clinical-history LR workbook reviewed
- No qualifying LR identified for c.5140G>T
Still missing
- A qualifying variant-level multifactorial clinical-history LR would be needed for PP4.
Sources
BS2 No point-based evidence from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BS2 uses a point-based framework in the absence of recessive disease features.
Evidence considered
- No qualifying BS2 data identified
Still missing
- Qualifying proband-level evidence scored under the ENIGMA BS2 framework would be needed for BS2.
Sources
BS4 No quantitative lack-of-segregation evidence for this variant was identified, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BS4 requires quantitative lack-of-segregation evidence with LR-based strength assignment.
Evidence considered
- No qualifying non-segregation LR identified
Still missing
- Family-level non-segregation data with LR-based scoring would be needed for BS4.
Sources
cspec ↗vcep_humu_40_1557_s001
BP5 No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history resource, so BP5 was not applied. Details ▾Hide ▴
Rule
ENIGMA BP5 requires a multifactorial clinical-data LR ≤0.48, with lower thresholds for stronger weights.
Evidence considered
- BRCA1 clinical-history LR workbook reviewed
- No qualifying LR identified for c.5140G>T
Still missing
- A qualifying variant-level multifactorial clinical-history LR of 0.48 or lower would be needed for BP5.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks PS2 not applicable
Sources
PM1 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks PM1 not applicable
Sources
PM4 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks PM4 not applicable
Sources
PM5 N/AIn the ENIGMA BRCA1 specification, PM5 is used for protein-termination variants in exons with established PM5_PTC applicability. This missense variant does not meet that variant-type requirement. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 is applied to qualifying PTC variants annotated as PVS1, not to this missense substitution.
Evidence considered
- Missense variant
- not a protein-termination variant
- Table 4 reviewed for PM5_PTC use
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks PM6 not applicable
Sources
PP2 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks PP2 not applicable
Sources
BP2 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks BP2 not applicable
Sources
BP3 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks BP3 not applicable
Sources
BP6 N/AThis criterion is not applicable in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- ENIGMA BRCA1 specification marks BP6 not applicable
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.5140G>T
- Protein (HGVS p.)
- NP_009225.1:p.(Val1714Phe)
- GRCh38
- chr17:43063886 C>A
- GRCh37
- chr17:41215903 C>A
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
—
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 within the BRCA1 BRCT repeats, a clinically important functional domain (aa 1650-1857). BayesDel no-AF is 0.482282, which is above the ENIGMA PP3 threshold of 0.28 for damaging protein effect, REVEL is 0.812, and SpliceAI is low at 0.09; together these data support a damaging protein effect rather than a splice-mediated explanation. Details ▾Hide ▴
Rule
ENIGMA applies PP3 for missense variants in a clinically important domain with BayesDel no-AF ≥0.28, or for predicted splice impact with SpliceAI ≥0.2.
Evidence considered
- BRCT domain location
- BayesDel no-AF 0.482282
- REVEL 0.812
- SpliceAI max delta 0.09
Sources
BP4 For a BRCA1 missense variant in a clinically important domain, BP4 requires BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower. Although SpliceAI is low at 0.09, BayesDel is 0.482282 and REVEL is 0.812, so computational evidence does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BP4 for missense variants in functional domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- BayesDel no-AF 0.482282
- REVEL 0.812
- SpliceAI max delta 0.09
Sources
BP7 BP7 in this framework requires qualifying RNA evidence and/or variant-type conditions that are not met here. This is a missense variant within the BRCA1 BRCT functional domain, SpliceAI is low at 0.09, and no RNA assay showing no transcript effect was identified, so BP7 was not applied. Details ▾Hide ▴
Rule
For BRCA1, BP7 use depends on variant type, domain context, and in some settings RNA evidence showing no damaging transcript effect.
Evidence considered
- Missense variant in BRCT domain
- SpliceAI max delta 0.09
- No RNA assay identified
Still missing
- A qualifying RNA study showing no damaging transcript effect would be needed to support BP7 in this context.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). REVEL score = 0.812. BayesDel score = 0.482282.
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/631061/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41215903-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43063886-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.5140…
- OncoKB ↗www.oncokb.org/gene/BRCA1/V1714F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.5140G%3ET
- 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 Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) 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 = 0.09). REVEL score = 0.812. BayesDel score = 0.482282.
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.