About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.301+7G>A, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PP3Supporting
PP3 · supporting
SpliceAI predicts splice impact for this intronic variant, with a maximum delta score of 0.29. This is above the ENIGMA PP3 threshold of 0.20 for intronic variants outside the canonical ±1,2 splice sites, so PP3 is met at Supporting strength.
Benign criteria applied · 2
BS3Strong
BS3 · strong
Well-established functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3 Strong for this intronic variant, citing no aberrant splicing in two studies and a calibrated study showing function similar to benign control variants with no functional impact.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Likely benign
ClinGen ENIGMA BRCA1/BRCA2 Specification v1.2.0 final-classification framework (Table 3 override with conflicting-evidence point system)
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
87 / 1,610,834 alleles
gnomAD v4.1: 87 / 1,610,834 alleles. Recorded AF 5.40093e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84762e-05; MAF= 0.00885%, 25/282562 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000193013; MAF= 0.01930%, 2/10362 alleles, homozygotes = 0); grpmax FAF= 0.00010876.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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 · 6 not met · 9 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.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar, where the overall classification is Benign with expert panel review.
This variant is present in gnomAD, with AF 0.0000885 in v2.1 (25/282562 alleles; grpmax FAF 0.00010876) and AF 0.0000540 in v4.1 (87/1610834 alleles; grpmax FAF 0.00005311), so it is not absent from controls and does not meet BA1.
Well-established functional evidence supports no damaging effect: ENIGMA Table 9 assigns BS3 Strong based on no aberrant splicing in two studies and a calibrated study showing no functional impact.
In silico splicing prediction is conflicting with the functional evidence, because SpliceAI gives a maximum delta score of 0.29, which exceeds the ENIGMA PP3 threshold of 0.20 and argues against BP4.
No criteria match.
Met · 3
PP3 SupportingSpliceAI predicts splice impact for this intronic variant, with a maximum delta score of 0.29. This is above the ENIGMA PP3 threshold of 0.20 for intronic variants outside the canonical ±1,2 splice sites, so PP3 is met at Supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PP3 applies to intronic variants outside ±1,2 when SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.29
- ENIGMA PP3 threshold for splicing is ≥0.2
Sources
BS3 StrongWell-established functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3 Strong for this intronic variant, citing no aberrant splicing in two studies and a calibrated study showing function similar to benign control variants with no functional impact. Details ▾Hide ▴
Rule
BS3 applies when well-established functional studies show no damaging effect on protein function, including calibrated studies that incorporate mRNA and protein effects.
Evidence considered
- ENIGMA Table 9: BS3 Strong
- Supplementary tables: no aberration in splicing studies
- functional classification: no functional impact
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗
Not met · 6 · evaluated, threshold not reached
PVS1 BRCA1 is a gene in which loss of function is an established disease mechanism, but this variant is an intronic +7 substitution rather than a nonsense, frameshift, or canonical ±1,2 splice-site variant. Available functional evidence shows no aberrant splicing and no functional impact, so PVS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 applies to null variants and to RNA evidence showing damaging loss-of-function at an appropriate strength.
Evidence considered
- BRCA1 PVS1 gene gate eligible
- c.301+7G>A is non-canonical intronic
- ENIGMA Table 9 assigns BS3 Strong with no aberration/no functional impact
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_table9_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗
PS3 Available functional studies do not support a damaging effect. ENIGMA Table 9 summarizes this variant as showing no aberrant splicing in two studies and no functional impact in a calibrated study, so PS3 was not met. Details ▾Hide ▴
Rule
PS3 requires well-established studies showing a damaging effect.
Evidence considered
- ENIGMA Table 9: no aberration
- 2 studies
- calibrated functional result: no functional impact
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000885 (25/282562 alleles; grpmax FAF 0.00010876) and in gnomAD v4.1 at AF 0.0000540 (87/1610834 alleles; grpmax FAF 0.00005311), so the ENIGMA PM2 absence threshold is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD non-cancer controls with adequate coverage.
Evidence considered
- gnomAD v2.1 total AF 8.84762e-05
- gnomAD v4.1 total AF 5.40093e-05
Sources
BA1 Population data do not reach the ENIGMA BA1 threshold. The observed grpmax FAF is 0.00010876 in gnomAD v2.1 and 0.00005311 in gnomAD v4.1, both below the BA1 cutoff of 0.001. Details ▾Hide ▴
Rule
BA1 requires FAF >0.001.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00010876
- gnomAD v4.1 grpmax FAF 0.00005311
Sources
BP4 BP4 is not met because SpliceAI predicts splice impact, with a maximum delta score of 0.29. This is above the ENIGMA benign threshold of 0.10 for intronic variants outside the canonical splice sites. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP4 applies to non-canonical intronic variants only when SpliceAI ≤0.1.
Evidence considered
- SpliceAI max delta score 0.29
- ENIGMA BP4 threshold is ≤0.1
Sources
BP7 This intronic +7 variant is in a position that can be considered for BP7, but BP7 Supporting requires BP4 and BP4 is not met because SpliceAI is 0.29, above the benign threshold of 0.10. The available non-damaging functional evidence is captured under BS3 rather than BP7. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP7 Supporting for intronic variants at or beyond +7/-21 requires BP4.
Evidence considered
- Intronic +7 position
- SpliceAI max delta score 0.29
- ENIGMA Table 9 assigns BS3 Strong
Sources
Not assessed · 9 · no assessment recorded
PS1 No evidence was identified showing that this variant has the same established pathogenic protein or splicing effect as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PS1 for same protein or splicing effect as an established pathogenic reference variant.
Evidence considered
- ENIGMA PS1 requires the same established protein or splicing effect as a known pathogenic/likely pathogenic variant
Still missing
- No matched reference pathogenic splicing variant with the same proven effect was identified.
Sources
PS4 No case-control evidence was identified showing a statistically significant increase of this variant in affected individuals compared with controls, so PS4 was not assessed. Details ▾Hide ▴
Rule
PS4 requires case-control evidence with p≤0.05 and OR≥4, with lower confidence interval excluding 2.0.
Evidence considered
- ClinVar observations do not provide qualifying ENIGMA PS4 case-control evidence
Still missing
- No qualifying odds ratio and p-value data were identified.
Sources
PM3 No evidence was identified for BRCA1-related Fanconi anemia with qualifying co-occurring variants in the same gene, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 in ENIGMA BRCA1/2 is used for recessive Fanconi anemia cases with point-based co-occurrence evidence.
Evidence considered
- ENIGMA PM3 is specific to BRCA1/2-related Fanconi anemia context
Still missing
- No recessive disease phenotype or trans-phase co-occurrence data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 in ENIGMA BRCA1/2 requires quantitative segregation likelihood ratios.
Evidence considered
- ENIGMA PP1 requires quantitative segregation evidence
Still missing
- No segregation likelihood ratio was identified.
Sources
PP4 No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
PP4 in ENIGMA BRCA1/2 requires a multifactorial likelihood ratio of at least 2.08.
Evidence considered
- BRCA1 clinical-history LR workbook showed no exact c.301+7G>A match
Still missing
- No exact BRCA1 clinical-history LR workbook match was identified for this variant.
Sources
BS1 This variant is present in gnomAD, but the available summaries do not establish a non-founder population filter allele frequency that clearly exceeds the ENIGMA BS1 thresholds. BS1 was therefore not applied from the current evidence summary. Details ▾Hide ▴
Rule
BS1 requires FAF above ENIGMA thresholds in non-founder population(s).
Evidence considered
- Variant present in gnomAD v2.1 and v4.1
- available summaries report overall/grpmax FAF without a clear qualifying non-founder FAF
Still missing
- Non-founder population-specific FAF needed for direct BS1 application.
Sources
BS2 No evidence was identified showing qualifying observations in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 in ENIGMA BRCA1/2 uses point-based evidence in the Fanconi anemia context.
Evidence considered
- ENIGMA BS2 is specific to absence of recessive disease features with point assignment
Still missing
- No point-based BS2 proband data were identified.
Sources
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 in ENIGMA BRCA1/2 requires a quantitative segregation likelihood ratio in the benign direction.
Evidence considered
- ENIGMA BS4 requires quantitative segregation evidence
Still missing
- No segregation likelihood ratio in the benign direction was identified.
Sources
BP5 No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 in ENIGMA BRCA1/2 requires a multifactorial likelihood ratio of 0.48 or lower.
Evidence considered
- BRCA1 clinical-history LR workbook showed no exact c.301+7G>A match
Still missing
- No exact BRCA1 clinical-history LR workbook match was identified for this variant.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PS2 as not applicable
Sources
PM1 N/APM1 is not applicable under the BRCA1 ENIGMA specification for this intronic variant type. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PM1 as not applicable
Sources
PM4 N/APM4 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PM4 as not applicable
Sources
PM5 N/AUnder the BRCA1 ENIGMA specification, PM5 is used for protein-termination-codon variants in eligible exons. This intronic +7 variant is not a protein-termination-codon variant, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PM5 is applied to eligible PTC variants by exon.
Evidence considered
- ENIGMA PM5 is specified here as PM5_PTC for protein-termination-codon variants
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PM6 as not applicable
Sources
PP2 N/APP2 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PP2 as not applicable
Sources
PP5 N/APP5 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PP5 as not applicable
Sources
BP1 N/ABP1 applies to silent, missense, or in-frame variants outside clinically important domains when no splicing effect is predicted. This intronic variant does not fit that rule, so BP1 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP1 is restricted to specified coding variant classes.
Evidence considered
- ENIGMA BP1 is defined for silent/missense/in-frame variants
- not intronic variants
Sources
BP2 N/ABP2 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks BP2 as not applicable
Sources
BP3 N/ABP3 is not applicable under the BRCA1 ENIGMA specification for this review. Details ▾Hide ▴
Rule
Not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks BP3 as not applicable
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.301+7G>A
- Protein (HGVS p.)
- NP_009225.1:p.?
- GRCh38
- chr17:43104861 C>T
- GRCh37
- chr17:41256878 C>T
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
87 / 1,610,834 alleles
AF 5.4e-05 · 0 homozygotes · FAF 5.31e-05
gnomAD v2.1
25 / 282,562 alleles
AF 8.85e-05 · 0 homozygotes · FAF 0.000109
By genetic ancestry
gnomAD v4.1
AF 5.4e-05 · 87 / 1,610,834 alleles · 0 hom · FAF 5.3e-05
| Ashkenazi Jewish4 / 29,586 | 0.00014 |
| European (non-Finnish)77 / 1,177,260 | 6.5e-05 |
| Remaining individuals3 / 62,376 | 4.8e-05 |
| European (Finnish)3 / 63,922 | 4.7e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, African/African American.
gnomAD v2.1
AF 8.8e-05 · 25 / 282,562 alleles · 0 hom · FAF 0.00011
| Ashkenazi Jewish2 / 10,362 | 0.00019 |
| European (non-Finnish)21 / 128,976 | 0.00016 |
| Remaining individuals1 / 7,204 | 0.00014 |
| European (Finnish)1 / 25,058 | 4e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, Admixed American, East Asian, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.40093e-05; MAF= 0.00540%, 87/1610834 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000135199; MAF= 0.01352%, 4/29586 alleles, homozygotes = 0); grpmax FAF= 5.311e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84762e-05; MAF= 0.00885%, 25/282562 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000193013; MAF= 0.01930%, 2/10362 alleles, homozygotes = 0); grpmax FAF= 0.00010876.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSpliceAI predicts splice impact for this intronic variant, with a maximum delta score of 0.29. This is above the ENIGMA PP3 threshold of 0.20 for intronic variants outside the canonical ±1,2 splice sites, so PP3 is met at Supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PP3 applies to intronic variants outside ±1,2 when SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score 0.29
- ENIGMA PP3 threshold for splicing is ≥0.2
Sources
BP4 BP4 is not met because SpliceAI predicts splice impact, with a maximum delta score of 0.29. This is above the ENIGMA benign threshold of 0.10 for intronic variants outside the canonical splice sites. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP4 applies to non-canonical intronic variants only when SpliceAI ≤0.1.
Evidence considered
- SpliceAI max delta score 0.29
- ENIGMA BP4 threshold is ≤0.1
Sources
BP7 This intronic +7 variant is in a position that can be considered for BP7, but BP7 Supporting requires BP4 and BP4 is not met because SpliceAI is 0.29, above the benign threshold of 0.10. The available non-damaging functional evidence is captured under BS3 rather than BP7. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP7 Supporting for intronic variants at or beyond +7/-21 requires BP4.
Evidence considered
- Intronic +7 position
- SpliceAI max delta score 0.29
- ENIGMA Table 9 assigns BS3 Strong
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29).
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
87 / 1,610,834 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/37499/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41256878-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43104861-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.301%…
- OncoKB ↗www.oncokb.org/gene/BRCA1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.301+7G%3EA
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= 5.40093e-05; MAF= 0.00540%, 87/1610834 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000135199; MAF= 0.01352%, 4/29586 alleles, homozygotes = 0); grpmax FAF= 5.311e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.84762e-05; MAF= 0.00885%, 25/282562 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.000193013; MAF= 0.01930%, 2/10362 alleles, homozygotes = 0); grpmax FAF= 0.00010876.
ClinVar
This variant has been reported in ClinVar as Benign (11 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign 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 = 0.29).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).