About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.80+5G>C, 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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
This intronic variant lies outside the native donor ±1,2 splice positions, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This is below the BRCA1 BP4 threshold of 0.1 for no predicted splice impact, so BP4 is met at Supporting strength.
Recorded classification: Uncertain significance
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 criteria-combination framework (official CSPEC/VCEP final-classification framework 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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: 1 met · 6 not met · 10 not assessed · 11 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.80+5G>C (NP_009225.1:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance without expert panel review.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports rarity in population databases.
SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the BRCA1 PP3 threshold of 0.2 and within the BP4 no-splice-impact threshold of 0.1 for intronic variants outside the native donor ±1,2 positions.
No criteria match.
Met · 1
BP4 SupportingThis intronic variant lies outside the native donor ±1,2 splice positions, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This is below the BRCA1 BP4 threshold of 0.1 for no predicted splice impact, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BP4_Supporting applies to intronic variants outside donor/acceptor ±1,2 with SpliceAI ≤0.1.
Evidence considered
- Variant location is c.80+5.
- SpliceAI max delta score = 0.00
- which is ≤0.1.
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This intronic variant is at donor position +5, not at the canonical ±1,2 splice site positions used for BRCA1 PVS1 application, and no variant-specific RNA study showing an abnormal transcript with loss-of-function consequence was identified. Available evidence therefore does not support applying PVS1 for this variant at this time. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PVS1 applies to null variants including canonical splice donor/acceptor ±1,2 variants, or to well-established mRNA evidence supporting a damaging splice effect at an appropriate strength.
Evidence considered
- BRCA1 is eligible for PVS1 under the ENIGMA specification.
- The variant is not a canonical ±1
- 2 splice-site change.
- No exact c.80+5G>C RNA result was identified in the reviewed BRCA1 VCEP materials.
Still missing
- Variant-specific RNA assay data would be needed to determine whether this change causes a loss-of-function transcript.
- A validated study showing the transcript consequence and proportion of abnormal splicing would help resolve whether RNA-based PVS1 evidence is applicable.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PS1 No previously classified pathogenic or likely pathogenic variant with the same demonstrated splice effect as this variant was identified. A different BRCA1 change at the same +5 position has published splice evidence, but that is not sufficient to show that c.80+5G>C has the same splice consequence. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PS1 for intronic variants requires the same predicted or demonstrated splice impact as a previously classified pathogenic or likely pathogenic variant, with strength depending on the comparator and context.
Evidence considered
- PS1 for intronic variants requires the same predicted or demonstrated impact on splicing as a previously classified pathogenic reference variant.
- No exact c.80+5G>C comparator with matched splice outcome was identified.
Still missing
- A validated comparator with the same demonstrated splice outcome would be needed to support PS1 under the BRCA1 specification.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00. This is below the BRCA1 PP3 threshold of 0.2, so computational evidence does not support a predicted splice-disrupting effect. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PP3 for intronic variants outside donor/acceptor ±1,2 requires SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score = 0.00.
Sources
BA1 This variant is absent from the reviewed population datasets and therefore is well below the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BA1 requires filter allele frequency >0.1% in gnomAD non-founder populations.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BS1 This variant is absent from the reviewed population datasets and therefore is below the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%. BS1 is not met. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BS1 requires filter allele frequency >0.002% for Supporting or >0.01% for Strong in gnomAD non-founder populations.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
BP7 SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BRCA1 BP7_Supporting for intronic variants is limited to positions at or beyond +7 or -21 when BP4 is met. This variant is at +5, so BP7 is not met, and no RNA study showing normal splicing was identified for BP7_Strong. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BP7_Supporting for intronic variants requires location at or beyond +7/-21 with BP4 met; BP7_Strong requires well-established RNA evidence showing no damaging splice effect.
Evidence considered
- Variant location is c.80+5.
- SpliceAI max delta score = 0.00.
- No exact benign RNA study for c.80+5G>C was identified.
Sources
Not assessed · 10 · no assessment recorded
PS3 No calibrated functional study for c.80+5G>C was identified in the reviewed BRCA1 functional tables. Published functional evidence was found for nearby splice-site variants, but not for this exact nucleotide change. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PS3 requires well-established functional evidence supportive of a damaging effect; for intronic variants this must be based on assays measuring relevant splicing and/or combined RNA-protein effect as specified.
Evidence considered
- No exact c.80+5G>C entry was identified in the BRCA1 functional assay tables reviewed.
Still missing
- An exact variant-specific functional or RNA study is needed to assess PS3.
Sources
PS4 No case-control or statistically enriched affected-individual data were identified for this variant. The available ClinVar record does not provide evidence meeting the BRCA1 PS4 threshold. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PS4 requires significant enrichment in affected individuals compared with controls with p≤0.05 and OR≥4, with the lower confidence interval excluding 2.0.
Evidence considered
- ClinVar shows limited single-submitter germline reporting.
- No qualifying PS4 study was identified.
Still missing
- Case-control data or a validated odds ratio meeting ENIGMA PS4 thresholds would be needed.
Sources
PM2 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity. However, BRCA1 ENIGMA PM2_Supporting requires absence from gnomAD v2.1 and v3.1 with adequate regional read depth, and the needed v3.1/depth documentation was not directly available here. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PM2_Supporting requires absence from gnomAD v2.1 and v3.1 in outbred controls with average read depth ≥25 around the variant.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Still missing
- Direct confirmation of absence in gnomAD v3.1 and average regional read depth ≥25 would be needed to apply PM2_Supporting strictly under the ENIGMA rule.
Sources
PM3 No evidence was identified that this variant has been observed in trans with another BRCA1 pathogenic variant in a person with BRCA1-related Fanconi anemia. Available data do not support PM3 assessment. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PM3 is reserved for BRCA1- or BRCA2-related Fanconi anemia with point-based trans evidence.
Evidence considered
- No qualifying recessive-disease trans observations were identified.
Still missing
- Documented trans observations in a proband with BRCA1-related Fanconi anemia would be needed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PP1 requires quantitative co-segregation evidence meeting defined likelihood-ratio thresholds.
Evidence considered
- No pedigree or co-segregation evidence was identified.
Still missing
- Family-based co-segregation data with quantitative likelihood ratios would be needed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP4 No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so PP4 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PP4 is used only for calibrated multifactorial clinical likelihood ratios meeting defined thresholds.
Evidence considered
- The BRCA1 clinical-history LR workbook did not contain an entry for c.80+5G>C.
Still missing
- An exact variant-level multifactorial or clinical-history likelihood ratio meeting ENIGMA thresholds would be needed.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrvcep_pmid_31853058_li_2020_geneticsinmedicinePMID:31853058 ↗
BS2 No point-based evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia as required by the BRCA1 ENIGMA framework. BS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BS2 uses a point-based framework in the absence of features of recessive disease.
Evidence considered
- No qualifying BS2 data were identified.
Still missing
- Point-based BRCA1/2 Fanconi anemia exclusion data would be needed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS3 No well-established functional study showing normal splicing or normal BRCA1 function for c.80+5G>C was identified. BS3 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BS3 requires well-established studies showing no damaging effect on protein function, or BP7 at appropriate strength for mRNA-only benign splice evidence.
Evidence considered
- No exact c.80+5G>C benign functional entry was identified in the reviewed functional tables.
Still missing
- An exact variant-specific study showing no damaging effect would be needed.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BS4 requires quantitative lack-of-segregation evidence meeting defined likelihood-ratio thresholds.
Evidence considered
- No family non-segregation evidence was identified.
Still missing
- Quantitative non-segregation evidence with likelihood-ratio support would be needed.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP5 No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so BP5 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BP5 is used only for calibrated multifactorial clinical likelihood ratios supporting a benign direction.
Evidence considered
- The BRCA1 clinical-history LR workbook did not contain an entry for c.80+5G>C.
Still missing
- An exact variant-level clinical likelihood ratio at or below the ENIGMA BP5 thresholds would be needed.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrvcep_pmid_31853058_li_2020_geneticsinmedicinePMID:31853058 ↗
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- PS2 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
PM1 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification because domain-based evidence is incorporated through other rules rather than used as a separate PM1 code. Details ▾Hide ▴
Evidence considered
- PM1 is marked not applicable by the BRCA1 ENIGMA specification.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM4 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- PM4 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
PM5 N/AFor BRCA1, PM5 is repurposed for protein-truncating variants already annotated as PVS1. This intronic splice-region variant is not eligible for that PM5 framework. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PM5 applies to protein termination codon variants in eligible exons as additional weight for PVS1-annotated truncating variants.
Evidence considered
- PM5 candidates artifact marks this case as not eligible for classic same-residue PM5.
- BRCA1 ENIGMA PM5 is used for PTC variants in eligible exons.
Sources
PM6 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- PM6 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
PP2 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- PP2 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
PP5 VCEPThis criterion is not for use in the BRCA1 ENIGMA specification. Details ▾Hide ▴
BP1 N/ABP1 in the BRCA1 ENIGMA specification applies to silent, missense, or in-frame coding variants outside clinically important domains with no predicted splice impact. This intronic variant is not eligible. Details ▾Hide ▴
Evidence considered
- The variant is intronic rather than silent
- missense
- or in-frame.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP2 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- BP2 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
BP3 VCEPThis criterion is not applicable in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Evidence considered
- BP3 is listed as not applicable by the BRCA1 ENIGMA specification.
Sources
BP6 VCEPThis criterion is not for use in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.80+5G>C
- Protein (HGVS p.)
- NP_009225.1:p.?
- GRCh38
- chr17:43124012 C>G
- GRCh37
- chr17:41276029 C>G
- ClinVar
- 433683
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
—
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingThis intronic variant lies outside the native donor ±1,2 splice positions, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This is below the BRCA1 BP4 threshold of 0.1 for no predicted splice impact, so BP4 is met at Supporting strength. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BP4_Supporting applies to intronic variants outside donor/acceptor ±1,2 with SpliceAI ≤0.1.
Evidence considered
- Variant location is c.80+5.
- SpliceAI max delta score = 0.00
- which is ≤0.1.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00. This is below the BRCA1 PP3 threshold of 0.2, so computational evidence does not support a predicted splice-disrupting effect. Details ▾Hide ▴
Rule
BRCA1 ENIGMA PP3 for intronic variants outside donor/acceptor ±1,2 requires SpliceAI ≥0.2.
Evidence considered
- SpliceAI max delta score = 0.00.
Sources
BP7 SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BRCA1 BP7_Supporting for intronic variants is limited to positions at or beyond +7 or -21 when BP4 is met. This variant is at +5, so BP7 is not met, and no RNA study showing normal splicing was identified for BP7_Strong. Details ▾Hide ▴
Rule
BRCA1 ENIGMA BP7_Supporting for intronic variants requires location at or beyond +7/-21 with BP4 met; BP7_Strong requires well-established RNA evidence showing no damaging splice effect.
Evidence considered
- Variant location is c.80+5.
- SpliceAI max delta score = 0.00.
- No exact benign RNA study for c.80+5G>C was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 17576681 ↗Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.Buratti E et al. · 2007No paper-specific finding is recorded.
-
PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
-
PMID 9536098 ↗Statistical features of human exons and their flanking regions.Zhang MQ · 1998No paper-specific finding is recorded.
-
PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.American Society of Clinical Oncology · 2003No paper-specific finding is recorded.
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
-
PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
-
PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
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/433683/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41276029-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43124012-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43124012-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.80%2…
- OncoKB ↗www.oncokb.org/gene/BRCA1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.80+5G%3EC
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 433683)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).