About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.5407-10G>A, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PP3Supporting
PP3 · supporting
Splice prediction supports an abnormal splicing effect. SpliceAI shows a maximum delta score of 1.00, which is above the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites, so PP3 is met at Supporting strength.
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: Uncertain significance
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 criteria-combination framework: applied criteria PP3 supporting and PP5 supporting do not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Uncertain Significance.
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
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79152e-06; MAF= 0.00088%, 1/113746 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.
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: 2 met · 8 not met · 8 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.5407-10G>A (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, where the current aggregate classification is Likely Pathogenic with expert-panel review.
This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06), which is too low for benign population criteria but does not satisfy the BRCA1 ENIGMA requirement for complete absence from gnomAD for PM2.
In published BRCA1 functional and RNA studies, this variant showed retention of 8 nucleotides from intron 22 and partial functional impact rather than a clearly damaging or clearly benign result, so the ENIGMA BRCA1 functional tables indicate that PS3 and BS3 are not met.
SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 1.00, which exceeds the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites and supports PP3 at Supporting strength.
No criteria match.
Met · 2
PP3 SupportingSplice prediction supports an abnormal splicing effect. SpliceAI shows a maximum delta score of 1.00, which is above the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites, so PP3 is met at Supporting strength. Details ▾Hide ▴
Rule
Apply PP3_Supporting for intronic variants outside donor/acceptor 1,2 positions when SpliceAI is >=0.20.
Evidence considered
- SpliceAI max delta score 1.00.
- Variant is intronic at c.5407-10
- outside +/-1
- 2.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 8 · evaluated, threshold not reached
PVS1 This intronic variant is outside the canonical +/-1,2 splice positions, so it does not qualify for default PVS1 application. Available BRCA1 functional/splicing data show retention of 8 nucleotides from intron 22 with partial functional impact rather than a clear loss-of-function result, so current evidence does not support PVS1 or PVS1(RNA). Details ▾Hide ▴
Rule
BRCA1 ENIGMA PVS1 applies to canonical splice variants or other LoF events, and mRNA-only evidence may support PVS1(RNA) only when it demonstrates a damaging loss-of-function effect.
Evidence considered
- Variant is non-canonical intronic (-10).
- Table 9 lists this exact variant with partial functional impact and states PS3/BS3 not met.
- Published RNA data describe retention of 8 nt of intron 22.
Still missing
- A quantitative transcript assessment showing a clearly loss-of-function splicing outcome would be needed to support PVS1(RNA) weighting.
Sources
cspec ↗pvs1_variant_assessmentvcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:31143303 ↗
PS3 Published functional and RNA studies for this exact variant showed partial impact rather than a clearly damaging effect. The BRCA1 ENIGMA functional table therefore indicates that PS3 is not met for this variant. Details ▾Hide ▴
Rule
PS3 requires well-established functional evidence supportive of a damaging effect.
Evidence considered
- Exact variant appears in BRCA1 Table 9.
- Table 9 states partial impact and PS3/BS3 not met.
- RNA study reports retention of 8 nt of intron 22.
Still missing
- No additional calibrated study showing a clearly damaging effect beyond the intermediate/partial result was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:31143303 ↗
PM2 This variant is not absent from population databases. It is seen once in gnomAD v2.1 (1/251448 alleles; AF 3.98e-06) even though it is absent from gnomAD v4.1, so the BRCA1 ENIGMA requirement for absence from gnomAD is not met. Details ▾Hide ▴
Rule
PM2_Supporting requires absence from gnomAD in the specified non-cancer datasets.
Evidence considered
- gnomAD v2.1 total AC 1/AN 251448.
- gnomAD v4.1 absent.
Still missing
- None from currently available population data.
Sources
BA1 Population frequency does not meet the BRCA1 stand-alone benign threshold. The variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1, far below the BA1 filter allele frequency threshold of greater than 0.1%. Details ▾Hide ▴
Rule
BA1 requires filter allele frequency >0.1% in an allowed gnomAD non-founder population.
Evidence considered
- gnomAD v2.1 AF 3.98e-06.
- gnomAD v4.1 absent.
Sources
BS1 Population frequency does not meet the BRCA1 benign strong or supporting thresholds. The observed gnomAD v2.1 allele frequency of 3.98e-06 is below the BS1 supporting threshold of greater than 0.002%, and the variant is absent from gnomAD v4.1. Details ▾Hide ▴
Rule
BS1 requires filter allele frequency above the BRCA1 benign thresholds.
Evidence considered
- gnomAD v2.1 AF 3.98e-06.
- gnomAD v4.1 absent.
Sources
BS3 Available functional and RNA evidence for this exact variant does not show a clearly normal effect. Instead, studies reported partial impact with retention of 8 nucleotides from intron 22, and the BRCA1 ENIGMA functional table indicates that BS3 is not met. Details ▾Hide ▴
Rule
BS3 requires well-established functional evidence supportive of no damaging effect.
Evidence considered
- Exact variant appears in BRCA1 Table 9.
- Table 9 states partial impact and PS3/BS3 not met.
- RNA study reports retention of 8 nt of intron 22.
Still missing
- No calibrated study showing normal or near-normal function/splicing was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:31143303 ↗
BP4 Computational evidence does not support a benign interpretation. For intronic BRCA1 variants outside the native +/-1,2 splice sites, BP4 requires SpliceAI 0.10 or lower, but this variant has a SpliceAI maximum delta score of 1.00. Details ▾Hide ▴
Rule
BP4 applies to intronic variants outside +/-1,2 only when SpliceAI is <=0.10.
Evidence considered
- SpliceAI max delta score 1.00.
Sources
BP7 Benign splice evidence is not supported. BP7_Supporting would require an intronic variant at or beyond +7/-21 together with BP4, and this variant is at c.5407-10 with SpliceAI 1.00, not BP4-compatible. RNA studies also showed abnormal splicing with retention of 8 intronic nucleotides, so BP7_Strong is not supported. Details ▾Hide ▴
Rule
BP7 requires either benign-supportive prediction for selected intronic/silent contexts or RNA evidence showing no damaging splicing effect.
Evidence considered
- Position c.5407-10 is within the conserved acceptor-region window used by ENIGMA BP7.
- SpliceAI max delta score 1.00.
- RNA study reports retention of 8 nt of intron 22.
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that this variant has the same established splicing consequence as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
Use PS1 for the same established protein or splicing consequence as a previously classified pathogenic/likely pathogenic variant.
Evidence considered
- BRCA1 ENIGMA PS1 permits use for variants with the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant.
Still missing
- A directly comparable pathogenic reference variant with the same experimentally supported splice outcome was not identified.
Sources
PS4 No case-control dataset or other prevalence analysis was identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed. Details ▾Hide ▴
Rule
PS4 requires statistically significant enrichment in affected individuals compared with controls.
Evidence considered
- ClinVar reports submissions and expert-panel classification
- but no usable PS4 case-control statistic was identified.
Still missing
- No odds ratio
- confidence interval
- or matched case-control evidence for this exact variant was identified.
Sources
PM3 No evidence was identified for this variant occurring with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
PM3 is used only for qualifying recessive BRCA1/2 Fanconi anemia observations.
Evidence considered
- BRCA1 ENIGMA restricts PM3 to BRCA1/2-related Fanconi anemia settings.
Still missing
- No recessive-disease phenotype and phase data were identified.
Sources
PP1 No informative segregation dataset was identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
PP1 requires quantitative co-segregation evidence meeting BRCA1 likelihood-ratio thresholds.
Evidence considered
- BRCA1 ENIGMA PP1 requires quantitative segregation evidence.
Still missing
- No quantitative segregation likelihood ratio was identified.
Sources
PP4 No usable BRCA1 clinical-history likelihood ratio was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
PP4 requires a qualifying BRCA1 multifactorial clinical likelihood ratio.
Evidence considered
- BRCA1 ENIGMA PP4 requires a calibrated multifactorial clinical likelihood ratio.
Still missing
- No exact variant match with an applicable pathogenic-direction likelihood ratio was identified in the available BRCA1 clinical-history materials.
Sources
BS2 No qualifying observations in individuals without features of BRCA1/2-related Fanconi anemia were identified for this variant, so BS2 was not assessed. Details ▾Hide ▴
Rule
BS2 requires enough qualifying observations to meet the BRCA1 point thresholds.
Evidence considered
- BRCA1 ENIGMA BS2 requires qualifying phenotype-negative observations.
Still missing
- No point-based BS2 evidence was identified.
Sources
BS4 No informative non-segregation dataset was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
BS4 requires quantitative non-segregation evidence meeting BRCA1 likelihood-ratio thresholds.
Evidence considered
- BRCA1 ENIGMA BS4 requires quantitative lack-of-segregation evidence.
Still missing
- No quantitative non-segregation likelihood ratio was identified.
Sources
BP5 No usable benign-direction BRCA1 clinical-history likelihood ratio was identified for this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
BP5 requires a qualifying BRCA1 multifactorial clinical likelihood ratio in the benign direction.
Evidence considered
- BRCA1 ENIGMA BP5 requires a calibrated multifactorial clinical likelihood ratio.
Still missing
- No exact variant match with an applicable benign-direction likelihood ratio was identified in the available BRCA1 clinical-history materials.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/APS2 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks PS2 as not applicable.
Sources
PM1 N/APM1 is not applicable in the BRCA1 ENIGMA specification for this variant type. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks PM1 as not applicable.
Sources
PM4 N/APM4 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks PM4 as not applicable.
Sources
PM5 N/APM5 in this BRCA1 ENIGMA framework is used for qualifying protein-termination-codon contexts or missense substitutions, and that situation was not identified for this intronic variant. Details ▾Hide ▴
Rule
PM5 is reserved for defined amino-acid substitution or PTC contexts in this specification.
Evidence considered
- Variant is intronic and not a protein-termination-codon variant qualifying under the BRCA1 PM5/PTC framework.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks PP2 as not applicable.
Sources
BP1 N/ABP1 in this BRCA1 ENIGMA framework applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice effect. That rule does not fit this intronic splice-predictive variant. Details ▾Hide ▴
Rule
BP1_Strong is limited to selected silent/missense/in-frame variants with no predicted splicing impact.
Evidence considered
- Variant is intronic.
- SpliceAI predicts splice impact.
Sources
BP2 N/ABP2 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks BP3 as not applicable.
Sources
BP6 N/ABP6 is not used in this BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP specification.
Evidence considered
- BRCA1 ENIGMA marks BP6 as not applicable.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.5407-10G>A
- Protein (HGVS p.)
- NP_009225.1:p.?
- GRCh38
- chr17:43047713 C>T
- GRCh37
- chr17:41199730 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
—
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
1 / 251,448 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v2.1
AF 4e-06 · 1 / 251,448 alleles · 0 hom
| European (non-Finnish)1 / 113,746 | 8.8e-06 |
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
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79152e-06; MAF= 0.00088%, 1/113746 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSplice prediction supports an abnormal splicing effect. SpliceAI shows a maximum delta score of 1.00, which is above the BRCA1 ENIGMA PP3 threshold of 0.20 for intronic variants outside the native +/-1,2 splice sites, so PP3 is met at Supporting strength. Details ▾Hide ▴
Rule
Apply PP3_Supporting for intronic variants outside donor/acceptor 1,2 positions when SpliceAI is >=0.20.
Evidence considered
- SpliceAI max delta score 1.00.
- Variant is intronic at c.5407-10
- outside +/-1
- 2.
Sources
BP4 Computational evidence does not support a benign interpretation. For intronic BRCA1 variants outside the native +/-1,2 splice sites, BP4 requires SpliceAI 0.10 or lower, but this variant has a SpliceAI maximum delta score of 1.00. Details ▾Hide ▴
Rule
BP4 applies to intronic variants outside +/-1,2 only when SpliceAI is <=0.10.
Evidence considered
- SpliceAI max delta score 1.00.
Sources
BP7 Benign splice evidence is not supported. BP7_Supporting would require an intronic variant at or beyond +7/-21 together with BP4, and this variant is at c.5407-10 with SpliceAI 1.00, not BP4-compatible. RNA studies also showed abnormal splicing with retention of 8 intronic nucleotides, so BP7_Strong is not supported. Details ▾Hide ▴
Rule
BP7 requires either benign-supportive prediction for selected intronic/silent contexts or RNA evidence showing no damaging splicing effect.
Evidence considered
- Position c.5407-10 is within the conserved acceptor-region window used by ENIGMA BP7.
- SpliceAI max delta score 1.00.
- RNA study reports retention of 8 nt of intron 22.
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
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 ↗
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/96950/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41199730-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43047713-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.5407…
- OncoKB ↗www.oncokb.org/gene/BRCA1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.5407-10G%3EA
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
This variant is present in gnomAD v2.1 (AF= 3.97697e-06; MAF= 0.00040%, 1/251448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79152e-06; MAF= 0.00088%, 1/113746 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Likely 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 = 1.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).