About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.135-1G>T, p.?
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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
PVS1Very strong
PVS1 · very strong
This BRCA1 variant affects the canonical splice acceptor at c.135-1. BRCA1 loss of function is an established disease mechanism, but the ENIGMA BRCA1 exon-specific table assigns c.135-1G>T to PVS1 (RNA) rather than full-strength generic PVS1 because available RNA data show aberrant splicing with exon 5 deletion, consistent with a damaging loss-of-function effect.
PP4Strong
PP4 · strong
Variant-specific clinical-history likelihood-ratio evidence supports pathogenicity. In the BRCA1 clinical-history LR table, this variant has LR 59.69 in 7 probands, which is above the ENIGMA PP4_Strong threshold of 18.7.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2 final-classification framework (Table 3 criteria-combination rules from final_classification_framework).
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
7 / 1,583,254 alleles
gnomAD v4.1: 7 / 1,583,254 alleles. Recorded AF 4.42127e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.13531e-06; MAF= 0.00071%, 2/280296 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56177e-05; MAF= 0.00156%, 2/128060 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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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 · 4 not met · 6 not assessed · 15 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.135-1G>T (NP_009225.1:p.?) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar with a pathogenic expert-panel classification.
This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 7.14e-06 (2/280296 alleles) and gnomAD v4.1 AF 4.42e-06 (7/1583254 alleles), which is below benign frequency thresholds but does not meet the ENIGMA PM2 requirement for absence from controls.
RNA and multifactorial evidence support a damaging splice effect for this variant, including exon 5 deletion in splicing studies, ENIGMA assignment of PVS1 (RNA), a reference-set posterior probability of 0.99999838416, and a BRCA1 clinical-history likelihood ratio of 59.69 across 7 probands, supporting PP4_Strong.
In silico splicing analysis predicts a strong splice effect, with a SpliceAI maximum delta score of 0.86, which is consistent with disruption of normal splicing but is not counted separately as PP3 because the same splice evidence is already captured under the PVS1 framework.
No criteria match.
Met · 3
PVS1 Very strongThis BRCA1 variant affects the canonical splice acceptor at c.135-1. BRCA1 loss of function is an established disease mechanism, but the ENIGMA BRCA1 exon-specific table assigns c.135-1G>T to PVS1 (RNA) rather than full-strength generic PVS1 because available RNA data show aberrant splicing with exon 5 deletion, consistent with a damaging loss-of-function effect. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 splice-site guidance with exon-specific Table 4 override
Evidence considered
- Canonical acceptor variant at -1 position
- BRCA1 loss of function eligible for PVS1
- ENIGMA Table 4 row for c.135-1G>T assigns PVS1 (RNA)
- Published splicing data report exon 5 deletion
Still missing
- If downstream scoring requires a mapped ACMG strength
- the exact weighting of the VCEP-specific PVS1 (RNA) code should be confirmed in the ENIGMA framework.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:20020529 ↗
PP4 StrongVariant-specific clinical-history likelihood-ratio evidence supports pathogenicity. In the BRCA1 clinical-history LR table, this variant has LR 59.69 in 7 probands, which is above the ENIGMA PP4_Strong threshold of 18.7. Details ▾Hide ▴
Rule
ENIGMA PP4 clinical-history LR thresholds
Evidence considered
- Clinical-history LR 59.68716765674412
- N probands 7
- PP4_Strong threshold 18.7
Sources
Not met · 4 · evaluated, threshold not reached
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 7.14e-06 (2/280296 alleles) and in gnomAD v4.1 at AF 4.42e-06 (7/1583254 alleles), so the ENIGMA PM2 requirement for absence from controls is not met. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from controls
Evidence considered
- gnomAD v2.1 total AF 7.13531e-06
- gnomAD v4.1 total AF 4.42127e-06
Sources
BA1 Population frequency does not meet the benign stand-alone threshold. The highest available group maximum filter allele frequency is 2.52e-06 in gnomAD v4.1, which is below the ENIGMA BA1 threshold of greater than 0.001. Details ▾Hide ▴
Rule
ENIGMA BA1 frequency threshold
Evidence considered
- gnomAD v4.1 grpmax FAF 2.52e-06
- BA1 threshold >0.001
Sources
BS1 Population frequency does not meet the benign strong or supporting thresholds. The highest available group maximum filter allele frequency is 2.52e-06 in gnomAD v4.1, which is below the ENIGMA BS1_Supporting threshold of greater than 2.0e-05 and below the BS1 threshold of greater than 1.0e-04. Details ▾Hide ▴
Rule
ENIGMA BS1 frequency thresholds
Evidence considered
- gnomAD v4.1 grpmax FAF 2.52e-06
- BS1_Supporting threshold >2.0e-05
- BS1 threshold >1.0e-04
Sources
BP5 Variant-specific clinical-history evidence does not support BP5. The observed LR is 59.69 in 7 probands, which is far above the BP5 benign threshold of less than or equal to 0.48 and instead supports PP4_Strong. Details ▾Hide ▴
Rule
ENIGMA BP5 clinical-history LR thresholds
Evidence considered
- Clinical-history LR 59.68716765674412
- BP5 threshold <=0.48
- N probands 7
Sources
Not assessed · 6 · no assessment recorded
PS1 Available evidence does not establish, within the retrieved materials, that this variant should receive PS1 based on a previously classified variant with the same proven splicing consequence at the weight required by the ENIGMA BRCA1 rules. Details ▾Hide ▴
Rule
ENIGMA PS1 splice-equivalence rule
Evidence considered
- PS1 is VCEP-applicable for same predicted/proven splicing impact
- but no qualifying matched comparator was confirmed
Still missing
- A variant-level ENIGMA Table 5 or equivalent same-splice-impact match was not identified in the retrieved materials.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been reported in affected individuals, but no ethnicity-matched case-control analysis with p-value less than or equal to 0.05 and odds ratio at least 4, with the lower confidence interval excluding 2.0, was identified from the retrieved evidence. ENIGMA also directs clinical-history likelihood ratios to PP4 or BP5 rather than PS4. Details ▾Hide ▴
Rule
ENIGMA PS4 case-control requirement
Evidence considered
- ClinVar pathogenic/expert-panel observation
- No qualifying PS4 case-control statistics identified
- Clinical-history LR evidence redirected to PP4/BP5 by ENIGMA
Still missing
- No qualifying ENIGMA case-control dataset was identified.
Sources
PM3 No evidence was identified for co-occurrence with another BRCA1 variant in a proband with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be assessed from the available data. Details ▾Hide ▴
Rule
ENIGMA PM3 Fanconi-anemia co-occurrence framework
Evidence considered
- No PM3-specific case data identified
Still missing
- No recessive phenotype or phase/co-occurrence evidence was identified.
Sources
PP1 No quantitative co-segregation likelihood ratio meeting ENIGMA PP1 thresholds was identified in the available evidence, so co-segregation support cannot be assigned. Details ▾Hide ▴
Rule
ENIGMA PP1 quantitative segregation thresholds
Evidence considered
- Segregation-themed publications were identified
- but no usable quantitative LR for PP1 was extracted
Still missing
- No case-level or family-level quantitative segregation analysis was retrieved.
Sources
BS2 No point-based evidence from unaffected individuals or from individuals lacking features of BRCA1-related Fanconi anemia was identified, so BS2 cannot be assessed from the available data. Details ▾Hide ▴
Rule
ENIGMA BS2 point-based framework
Evidence considered
- No BS2 case data identified
Still missing
- No BS2-specific point assignments or qualifying observations were identified.
Sources
BS4 No quantitative lack-of-segregation likelihood ratio meeting ENIGMA BS4 thresholds was identified in the available evidence, so BS4 cannot be assigned. Details ▾Hide ▴
Rule
ENIGMA BS4 quantitative segregation thresholds
Evidence considered
- Segregation-themed publications identified
- but no usable BS4 LR extracted
Still missing
- No family-level quantitative segregation analysis supporting lack of segregation was retrieved.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not used by the ENIGMA BRCA1 specification for this gene-disease context. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS2 applicability
Evidence considered
- PS2 listed as not applicable in BRCA1 ENIGMA specification
Sources
PS3 N/AAvailable functional evidence for this variant is RNA-based splicing evidence rather than a protein or combined protein-plus-RNA assay assigned under ENIGMA Table 9. Under the BRCA1 specification, damaging mRNA-only evidence is captured under PVS1 (RNA) rather than PS3. Details ▾Hide ▴
Rule
ENIGMA PS3 excludes mRNA-only damaging evidence from PS3 and redirects to PVS1 (RNA)
Evidence considered
- RNA/splicing evidence present
- No qualifying Table 9 PS3 assignment identified for this splice variant
Sources
PM1 N/AThis criterion is not applied as a standalone code in the ENIGMA BRCA1 specification and is instead incorporated into the bioinformatic framework for other variant types. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM1 applicability
Evidence considered
- PM1 marked not applicable in BRCA1 ENIGMA specification
Sources
PM4 N/AThis criterion is not used by the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM4 applicability
Evidence considered
- PM4 listed as not applicable in BRCA1 ENIGMA specification
Sources
PM5 N/AENIGMA PM5 in BRCA1 is used for protein-termination variants that are already annotated with PVS1 in exons where PM5_PTC is permitted. This splice variant is assigned PVS1 (RNA) rather than a PTC-based PVS1 code, so PM5_PTC is not applicable. Details ▾Hide ▴
Rule
ENIGMA PM5_PTC exon-specific rule
Evidence considered
- Exon 4(5) has PM5_Strong (PTC) framework
- Variant-specific row assigns PVS1 (RNA)
- not PTC-based PVS1
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not used by the ENIGMA BRCA1 specification for this gene-disease context. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM6 applicability
Evidence considered
- PM6 listed as not applicable in BRCA1 ENIGMA specification
Sources
PP2 N/AThis criterion is not used by the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP2 applicability
Evidence considered
- PP2 listed as not applicable in BRCA1 ENIGMA specification
Sources
PP3 N/ASpliceAI predicts a strong splice effect with a maximum delta score of 0.86, which is above the ENIGMA PP3 threshold of 0.2. However, the generic PVS1 scaffold and ENIGMA guidance state that PP3 should not be stacked when the same splice-effect evidence is already being used for PVS1 in a canonical splice variant, so PP3 is not additionally applied. Details ▾Hide ▴
Rule
ENIGMA PP3 splice prediction rule with no double-counting alongside PVS1
Evidence considered
- SpliceAI max delta score 0.86
- Canonical splice variant already captured under PVS1 framework
Sources
BS3 N/ANo well-established functional evidence showing no damaging effect was identified. Available RNA evidence supports abnormal splicing and is not benign evidence, so BS3 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BS3 functional evidence rule
Evidence considered
- RNA data indicate aberrant splicing with exon 5 deletion
- No benign Table 9 assignment identified
Sources
BP1 N/ABP1 applies to silent, missense, or in-frame variants outside clinically important domains without predicted splice impact. This canonical splice acceptor variant does not fit that rule. Details ▾Hide ▴
Rule
ENIGMA BP1 applicability by variant type
Evidence considered
- Variant type is canonical splice acceptor
Sources
BP2 N/AThis criterion is not used by the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP2 applicability
Evidence considered
- BP2 listed as not applicable in BRCA1 ENIGMA specification
Sources
BP3 N/AThis criterion is not used by the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP3 applicability
Evidence considered
- BP3 listed as not applicable in BRCA1 ENIGMA specification
Sources
BP4 N/ABP4 applies when computational evidence predicts no impact. SpliceAI shows a maximum delta score of 0.86, which is well above the ENIGMA no-impact threshold of 0.1, so BP4 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP4 splice prediction threshold
Evidence considered
- SpliceAI max delta score 0.86
- BP4 threshold <=0.1
Sources
BP6 N/AThis criterion is not used by the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP6 applicability
Evidence considered
- BP6 explicitly not applicable for this VCEP
Sources
BP7 N/ABP7 is a benign splicing code for variants with no damaging transcript effect. Available RNA evidence shows exon 5 deletion, and computational evidence predicts a strong splice effect with SpliceAI 0.86, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7 splicing framework
Evidence considered
- SpliceAI max delta score 0.86
- RNA studies show exon 5 deletion
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.135-1G>T
- Protein (HGVS p.)
- NP_009225.1:p.?
- GRCh38
- chr17:43106534 C>A
- GRCh37
- chr17:41258551 C>A
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
—
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
7 / 1,583,254 alleles
AF 4.42e-06 · 0 homozygotes · FAF 2.52e-06
gnomAD v2.1
2 / 280,296 alleles
AF 7.14e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 4.4e-06 · 7 / 1,583,254 alleles · 0 hom · FAF 2.5e-06
| European (non-Finnish)7 / 1,153,704 | 6.1e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 7.1e-06 · 2 / 280,296 alleles · 0 hom
| European (non-Finnish)2 / 128,060 | 1.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.42127e-06; MAF= 0.00044%, 7/1583254 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.06741e-06; MAF= 0.00061%, 7/1153704 alleles, homozygotes = 0); grpmax FAF= 2.52e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.13531e-06; MAF= 0.00071%, 2/280296 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56177e-05; MAF= 0.00156%, 2/128060 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts a strong splice effect with a maximum delta score of 0.86, which is above the ENIGMA PP3 threshold of 0.2. However, the generic PVS1 scaffold and ENIGMA guidance state that PP3 should not be stacked when the same splice-effect evidence is already being used for PVS1 in a canonical splice variant, so PP3 is not additionally applied. Details ▾Hide ▴
Rule
ENIGMA PP3 splice prediction rule with no double-counting alongside PVS1
Evidence considered
- SpliceAI max delta score 0.86
- Canonical splice variant already captured under PVS1 framework
Sources
BP4 N/ABP4 applies when computational evidence predicts no impact. SpliceAI shows a maximum delta score of 0.86, which is well above the ENIGMA no-impact threshold of 0.1, so BP4 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP4 splice prediction threshold
Evidence considered
- SpliceAI max delta score 0.86
- BP4 threshold <=0.1
Sources
BP7 N/ABP7 is a benign splicing code for variants with no damaging transcript effect. Available RNA evidence shows exon 5 deletion, and computational evidence predicts a strong splice effect with SpliceAI 0.86, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7 splicing framework
Evidence considered
- SpliceAI max delta score 0.86
- RNA studies show exon 5 deletion
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.86).
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
7 / 1,583,254 recorded alleles
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 ↗
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/37404/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41258551-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43106534-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.135-…
- OncoKB ↗www.oncokb.org/gene/BRCA1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=144952916
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.42127e-06; MAF= 0.00044%, 7/1583254 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.06741e-06; MAF= 0.00061%, 7/1153704 alleles, homozygotes = 0); grpmax FAF= 2.52e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.13531e-06; MAF= 0.00071%, 2/280296 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.56177e-05; MAF= 0.00156%, 2/128060 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as pathogenic (1 clinical laboratory) and as not provided (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.86).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV100524937, n = 1 times).