About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.67G>A, p.(Glu23Lys)
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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS3Strong
BS3 · strong
In a calibrated BRCA1 functional study, this variant showed protein function similar to benign control variants, and BRCA1 expert-panel materials assign BS3_Strong. Supplementary functional data list c.67G>A as having no functional impact.
BP4Supporting
BP4 · supporting
This missense variant lies in the BRCA1 RING domain and shows no predicted damaging effect under the BRCA1 computational rule. BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the splice threshold of 0.1, supporting BP4_Supporting.
Recorded classification: Likely benign
Applied the official ENIGMA BRCA1/BRCA2 v1.2 final-classification framework (Table 3 criteria-combination rules from the CSPEC/VCEP 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
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 5 not met · 9 not assessed · 12 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.67G>A (p.Glu23Lys, E23K) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with a single submitter interpretation of uncertain significance.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity in population databases.
In a calibrated BRCA1 functional study, this variant showed no functional impact and BRCA1 expert-panel materials assign BS3_Strong for c.67G>A.
Available computational evidence does not support a damaging effect under the BRCA1 ENIGMA rule: BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the threshold of 0.1; REVEL is 0.734 but is not the governing BRCA1 VCEP threshold for PP3/BP4.
No criteria match.
Met · 2
BS3 StrongIn a calibrated BRCA1 functional study, this variant showed protein function similar to benign control variants, and BRCA1 expert-panel materials assign BS3_Strong. Supplementary functional data list c.67G>A as having no functional impact. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS3 Strong
Evidence considered
- Table 9 assigns BS3 Strong for c.67G>A
- Supplementary Table 4 lists 'No functional impact'
- Findlay 2018 cited as calibrated functional evidence
Sources
BP4 SupportingThis missense variant lies in the BRCA1 RING domain and shows no predicted damaging effect under the BRCA1 computational rule. BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the splice threshold of 0.1, supporting BP4_Supporting. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 Supporting
Evidence considered
- BayesDel no-AF 0.0764379 <= 0.15
- SpliceAI max delta 0.00 <= 0.1
- Variant is in the BRCA1 RING domain
Sources
Not met · 5 · evaluated, threshold not reached
PS3 Available functional evidence does not support a damaging effect. In the reviewed BRCA1 functional datasets, this variant was reported as having no functional impact rather than an abnormal function pattern. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS3
Evidence considered
- Table 9 does not assign PS3 to c.67G>A
- Supplementary Table 4 lists c.67G>A as 'No functional impact'
Sources
PP3 This missense variant lies in the BRCA1 RING domain, but the computational thresholds for PP3 are not met. BayesDel no-AF is 0.076, which is below the BRCA1 PP3 threshold of 0.28, and SpliceAI is 0.00, which is below the splice threshold of 0.2. REVEL is 0.734, but the BRCA1 VCEP rule uses BayesDel and SpliceAI for PP3/BP4 adjudication. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 Supporting
Evidence considered
- BayesDel no-AF 0.0764379
- SpliceAI max delta 0.00
- REVEL 0.734
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BA1 Stand Alone
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS1
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP1 BP1_Strong requires a missense or similar variant outside a clinically important BRCA1 functional domain with no splice effect. This variant affects codon 23 in the BRCA1 RING domain, so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP1 Strong
Evidence considered
- Variant affects BRCA1 codon 23 in the RING domain
- SpliceAI max delta 0.00
Sources
Not assessed · 9 · no assessment recorded
PS1 No confirmed pathogenic or likely pathogenic comparator producing the same amino acid change was identified in the reviewed materials, so PS1 was not assessed from the currently available evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS1
Evidence considered
- BRCA1 VCEP PS1 requires a previously classified pathogenic or likely pathogenic comparator with the same protein or splice effect
Still missing
- A verified same-amino-acid pathogenic comparator would be needed to assess PS1.
Sources
PS4 No case-control study or quantified enrichment data showing that this variant is significantly more common in affected individuals than controls were identified, so PS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS4 requires significant enrichment in affected individuals
Evidence considered
- ClinVar shows a single submitter record without case-control quantification
Still missing
- Variant-specific odds ratio or other case-enrichment data meeting BRCA1 VCEP thresholds would be needed.
Sources
PM2 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is consistent with rarity. However, the reviewed materials did not provide the full BRCA1 VCEP PM2 control and coverage confirmation required to assign PM2_Supporting with confidence, so PM2 was not assessed in this pass. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM2_Supporting requires absence from controls with coverage requirements
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada
Still missing
- Confirm the required control dataset and regional coverage threshold under the BRCA1 VCEP framework before applying PM2_Supporting.
Sources
PM3 No evidence was identified that this variant has been observed in the biallelic Fanconi anemia context required for BRCA1 PM3 scoring, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM3
Evidence considered
- No qualifying BRCA1 Fanconi anemia evidence identified
Still missing
- Phase-confirmed BRCA1 biallelic observations with phenotype data would be needed.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
PP4 No variant-specific BRCA1 clinical-history likelihood ratio meeting PP4 thresholds was identified in the reviewed materials, so PP4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP4
Evidence considered
- No exact qualifying BRCA1 clinical-history LR was identified for c.67G>A
Still missing
- A validated variant-specific clinical-history or multifactorial likelihood ratio at or above the BRCA1 VCEP threshold would be needed.
Sources
BS2 No qualifying observations in unaffected individuals meeting the BRCA1 BS2 point-based framework were identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS2
Evidence considered
- No qualifying BS2 observations identified
Still missing
- Point-scored unaffected observations without Fanconi anemia features would be needed.
Sources
BS4 No lack-of-segregation data were identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS4
Evidence considered
- No qualifying non-segregation evidence identified
Still missing
- Quantified non-segregation data would be needed.
Sources
BP5 No variant-specific BRCA1 clinical-history likelihood ratio at or below the BP5 thresholds was identified in the reviewed materials, so BP5 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP5
Evidence considered
- No exact qualifying BRCA1 clinical-history LR was identified for c.67G>A
Still missing
- A validated variant-specific clinical-history or multifactorial likelihood ratio in the benign direction would be needed.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Glu23Lys), and does not fall into the BRCA1 null-variant categories used for PVS1. Available evidence does not support a truncating or canonical splice-site mechanism for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PVS1 applies to null variants or qualifying RNA evidence, not this missense change
Evidence considered
- Missense consequence p.(Glu23Lys)
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
Sources
PS2 VCEPThis BRCA1 specification marks PS2 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PS2 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
PM1 VCEPThis BRCA1 specification marks PM1 as not applicable for variant classification. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PM1 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
PM4 VCEPThis BRCA1 specification marks PM4 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PM4 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
PM5 N/AFor BRCA1 in this framework, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison. Because c.67G>A is a missense variant, PM5 is not applicable here. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM5_PTC framework
Evidence considered
- PM5 candidates file marks this case as ineligible for classic same-residue PM5
- BRCA1 PM5 is used for PTC logic in this specification
Sources
PM6 VCEPThis BRCA1 specification marks PM6 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PM6 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
PP2 VCEPThis BRCA1 specification marks PP2 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PP2 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
PP5 VCEPThis BRCA1 specification marks PP5 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 PP5 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
BP2 VCEPThis BRCA1 specification marks BP2 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 BP2 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
BP3 VCEPThis BRCA1 specification marks BP3 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 BP3 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
BP6 VCEPThis BRCA1 specification marks BP6 as not applicable. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 BP6 not applicable
Evidence considered
- Criterion listed as not applicable in the BRCA1 VCEP specification
Sources
BP7 N/ABP7 in this BRCA1 specification is used for silent or intronic variants, and this variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7
Evidence considered
- Variant type is missense rather than silent or intronic
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.67G>A
- Protein (HGVS p.)
- NP_009225.1:p.(Glu23Lys)
- GRCh38
- chr17:43124030 C>T
- GRCh37
- chr17:41276047 C>T
- ClinVar
- 867739
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
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
- 0.734
- BayesDel
- 0.076
How the predictions were used
BP4 SupportingThis missense variant lies in the BRCA1 RING domain and shows no predicted damaging effect under the BRCA1 computational rule. BayesDel no-AF is 0.076, which is at or below the BP4 threshold of 0.15, and SpliceAI is 0.00, which is at or below the splice threshold of 0.1, supporting BP4_Supporting. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 Supporting
Evidence considered
- BayesDel no-AF 0.0764379 <= 0.15
- SpliceAI max delta 0.00 <= 0.1
- Variant is in the BRCA1 RING domain
Sources
PP3 This missense variant lies in the BRCA1 RING domain, but the computational thresholds for PP3 are not met. BayesDel no-AF is 0.076, which is below the BRCA1 PP3 threshold of 0.28, and SpliceAI is 0.00, which is below the splice threshold of 0.2. REVEL is 0.734, but the BRCA1 VCEP rule uses BayesDel and SpliceAI for PP3/BP4 adjudication. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 Supporting
Evidence considered
- BayesDel no-AF 0.0764379
- SpliceAI max delta 0.00
- REVEL 0.734
Sources
BP7 N/ABP7 in this BRCA1 specification is used for silent or intronic variants, and this variant is a missense substitution, so BP7 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7
Evidence considered
- Variant type is missense rather than silent or intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.734. BayesDel score = 0.0764379.
4 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 14722926 ↗Novel germline mutations in the BRCA1 and BRCA2 genes in Indian breast and breast-ovarian cancer families.Valarmathi MT et al. · 2004No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
-
PMID 30209399 ↗Accurate classification of BRCA1 variants with saturation genome editing.Findlay GM et al. · 2018No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No 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
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB 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/867739/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41276047-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43124030-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43124030-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.67G%…
- OncoKB ↗www.oncokb.org/gene/BRCA1/E23K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.67G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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 (1 clinical laboratory). (ClinVarID = 867739)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.734. BayesDel score = 0.0764379.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.