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 with a maximum delta score of 0.29, which is above the ENIGMA BRCA1 PP3 threshold of 0.2 for intronic variants outside the ±1,2 splice positions. This supports PP3 at supporting strength.
Benign criteria applied · 2
BS3Strong
BS3 · strong
ENIGMA BRCA1 Table 9 assigns BS3 at strong strength for this variant. A calibrated functional study found function similar to benign control variants, and two RNA studies reported no aberrant splicing, supporting no damaging functional effect.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Likely benign
Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework used: Specification v1.2 Table 3 with the ENIGMA 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
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.
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 · 5 not met · 10 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 and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes), so it is not absent from population controls.
Functional evidence supports a benign effect: ENIGMA BRCA1 Table 9 assigns BS3_Strong for this variant, and RNA studies reported no aberrant splicing.
Computational splicing evidence predicts possible splice impact, with a SpliceAI maximum delta score of 0.29, which meets the ENIGMA BRCA1 PP3 threshold and does not meet the BP4 threshold.
No criteria match.
Met · 3
PP3 SupportingSpliceAI predicts splice impact with a maximum delta score of 0.29, which is above the ENIGMA BRCA1 PP3 threshold of 0.2 for intronic variants outside the ±1,2 splice positions. This supports PP3 at supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for predicted splicing when SpliceAI ≥0.2
Evidence considered
- SpliceAI DS_AG 0.21
- DS_DG 0.29
- max delta score 0.29.
- Variant position is intronic outside the canonical donor site.
Sources
BS3 StrongENIGMA BRCA1 Table 9 assigns BS3 at strong strength for this variant. A calibrated functional study found function similar to benign control variants, and two RNA studies reported no aberrant splicing, supporting no damaging functional effect. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS3 Strong from calibrated functional evidence showing no damaging effect
Evidence considered
- ENIGMA Table 9: BRCA1 c.301+7G>A = BS3 Strong.
- ST3: Steffensen 2014 (PMID 24667779) no aberration.
- ST3: Houdayer 2012 (PMID 22505045) no aberration.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗2250504524667779
Not met · 5 · evaluated, threshold not reached
PVS1 This intronic BRCA1 variant is at c.301+7, outside the canonical donor ±1,2 positions used for default PVS1 application, and available RNA studies reported no aberrant splicing. Available evidence does not support a loss-of-function transcript for this variant, so PVS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 applies to canonical splice-site or demonstrated loss-of-function RNA events; this +7 intronic variant lacks evidence for an abnormal loss-of-function transcript.
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the ENIGMA BRCA1 framework.
- The variant is not a nonsense
- frameshift
- or canonical ±1
- 2 splice variant.
- Supplementary splicing references list c.301+7G>A as showing no aberration in RNA studies.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗2250504524667779
PS3 Available functional evidence does not show a damaging effect. ENIGMA BRCA1 Table 9 instead records this variant as having function similar to benign control variants, and RNA studies reported no aberration. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence; the reviewed functional evidence is benign-direction.
Evidence considered
- ENIGMA Table 9 assigns c.301+7G>A to BS3 Strong rather than PS3.
- ST3 lists two RNA studies with no aberration.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗2250504524667779
PM2 This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes) with grpmax FAF 5.311e-05, so it is not absent from population controls and PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2_Supporting requires absence from controls; the variant is observed in gnomAD v4.1.
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: AF 5.4009289597810824e-05
- 87/1610834 alleles
- 0 homozygotes
- grpmax FAF 5.311e-05.
Sources
BA1 The observed gnomAD v4.1 grpmax FAF is 5.311e-05, which is below the ENIGMA BRCA1 BA1 threshold of 0.001. BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires FAF >0.001
Evidence considered
- gnomAD v4.1 grpmax FAF 5.311e-05.
Sources
BP4 For intronic variants outside the native donor and acceptor ±1,2 positions, ENIGMA BRCA1 requires SpliceAI 0.1 or less for BP4. This variant has a maximum SpliceAI delta score of 0.29, which is above that threshold, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for intronic variants requires SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.29.
Sources
Not assessed · 10 · no assessment recorded
PS1 No qualifying pathogenic reference variant with the same established splicing consequence was identified for this variant, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 allows PS1 for variants with the same proven protein or splicing effect as a classified pathogenic reference variant.
Still missing
- No directly reviewed ENIGMA Table 5-style same-splice-effect comparator was identified.
Sources
PS4 No case-control evidence showing significant enrichment in affected individuals was identified, so PS4 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 requires case-control enrichment data for PS4.
Still missing
- No reviewed case-control odds ratio or likelihood-ratio dataset was identified for this exact variant.
Sources
PM3 No evidence was identified for BRCA1-related Fanconi anemia with this variant observed in trans with another BRCA1 variant, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 reserves PM3 for BRCA1/2-related Fanconi anemia evidence.
Still missing
- No FA phenotype or in-trans observation data were reviewed.
Sources
PP1 No quantitative segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 requires quantitative cosegregation evidence for PP1.
Still missing
- No pedigree-level likelihood-ratio or cosegregation analysis was reviewed.
Sources
PP4 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified, so PP4 was not assessed. Details ▾Hide ▴
Evidence considered
- Exact match not found in the BRCA1 clinical-history LR workbook.
Still missing
- The reviewed BRCA1 clinical-history likelihood-ratio table did not contain an exact c.301+7G>A match.
Sources
BS1 Available population data show that this variant is present at low frequency in gnomAD v4.1, but the reviewed evidence did not establish a clearly qualifying non-founder filter allele frequency for separate BS1 application under the ENIGMA BRCA1 population framework. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF 5.4009289597810824e-05
- highest observed population AF reported in Ashkenazi Jewish samples.
Still missing
- A fully resolved non-founder FAF assessment under the ENIGMA BRCA1 BS1 rule was not available in the reviewed materials.
Sources
BS2 No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 uses a point-based recessive disease framework for BS2.
Still missing
- No qualifying trans observations or point-based BS2 evidence were reviewed.
Sources
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 requires quantitative segregation evidence for BS4.
Still missing
- No pedigree-level likelihood-ratio evidence against segregation was reviewed.
Sources
BP5 No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 BP5 thresholds was identified, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- Exact match not found in the BRCA1 clinical-history LR workbook.
Still missing
- The reviewed BRCA1 clinical-history likelihood-ratio table did not contain an exact c.301+7G>A match.
Sources
BP7 This variant is at +7, a position that can enter the ENIGMA BRCA1 BP7 framework, but BP4 is not met because SpliceAI is 0.29. RNA studies reported no aberration, and this benign functional evidence is already captured by BS3_Strong, so BP7 was not separately applied. Details ▾Hide ▴
Evidence considered
- Variant position c.301+7 falls at the edge of the BP7 intronic rule.
- SpliceAI max delta score 0.29 exceeds the BP4-compatible threshold.
- RNA studies reported no aberration
- and ENIGMA Table 9 assigns BS3 Strong.
Sources
cspec ↗spliceai ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗2250504524667779
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/AThis criterion is not used in the ENIGMA BRCA1 specification for BRCA1/2-related cancer interpretation. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PS2 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
PM1 N/APM1 is not applicable in the ENIGMA BRCA1 specification for this disease framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PM1 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
PM4 N/APM4 is not applicable in the ENIGMA BRCA1 specification for this disease framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PM4 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
PM5 N/AIn the ENIGMA BRCA1 specification, PM5 is used for protein-terminating variants in eligible exons or for qualifying missense/splice comparators, and this c.301+7G>A intronic variant does not meet those use conditions. Details ▾Hide ▴
Rule
Not a PM5_PTC-eligible variant
Evidence considered
- The variant is not a protein-terminating variant.
- No qualifying comparator evidence was identified.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis criterion is not used in the ENIGMA BRCA1 specification for BRCA1/2-related cancer interpretation. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PM6 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
PP2 N/APP2 is not applicable in the ENIGMA BRCA1 specification for this disease framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PP2 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
PP5 N/APP5 is not used in this ENIGMA BRCA1 framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- PP5 is listed as not applicable for this VCEP.
Sources
BP1 N/ABP1 in ENIGMA BRCA1 is used for silent, missense, or in-frame variants without predicted splice impact, and this variant is intronic. Details ▾Hide ▴
Rule
Variant type outside BP1 scope
Evidence considered
- The variant is intronic rather than missense
- silent
- or in-frame.
Sources
BP2 N/ABP2 is not applicable in the ENIGMA BRCA1 specification for this disease framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- BP2 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
BP3 N/ABP3 is not applicable in the ENIGMA BRCA1 specification for this disease framework. Details ▾Hide ▴
Rule
VCEP not applicable
Evidence considered
- BP3 is listed as not applicable in the ENIGMA BRCA1 specification.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3: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_007294.3. 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
87 / 1,610,834 alleles
AF 5.4e-05 · 0 homozygotes · FAF 5.31e-05
gnomAD v2.1
Allele count data not recorded
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.
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
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSpliceAI predicts splice impact with a maximum delta score of 0.29, which is above the ENIGMA BRCA1 PP3 threshold of 0.2 for intronic variants outside the ±1,2 splice positions. This supports PP3 at supporting strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for predicted splicing when SpliceAI ≥0.2
Evidence considered
- SpliceAI DS_AG 0.21
- DS_DG 0.29
- max delta score 0.29.
- Variant position is intronic outside the canonical donor site.
Sources
BP4 For intronic variants outside the native donor and acceptor ±1,2 positions, ENIGMA BRCA1 requires SpliceAI 0.1 or less for BP4. This variant has a maximum SpliceAI delta score of 0.29, which is above that threshold, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for intronic variants requires SpliceAI ≤0.1
Evidence considered
- SpliceAI max delta score 0.29.
Sources
BP7 This variant is at +7, a position that can enter the ENIGMA BRCA1 BP7 framework, but BP4 is not met because SpliceAI is 0.29. RNA studies reported no aberration, and this benign functional evidence is already captured by BS3_Strong, so BP7 was not separately applied. Details ▾Hide ▴
Evidence considered
- Variant position c.301+7 falls at the edge of the BP7 intronic rule.
- SpliceAI max delta score 0.29 exceeds the BP4-compatible threshold.
- RNA studies reported no aberration
- and ENIGMA Table 9 assigns BS3 Strong.
Sources
cspec ↗spliceai ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:22505045 ↗PMID:24667779 ↗2250504524667779
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_007294.3%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
Absent from gnomAD v2.1.
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).