About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.2063del, p.(Thr688LysfsTer13)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This variant is a frameshift deletion in BRCA1 exon 10 (legacy exon 11) predicted to cause p.(Thr688LysfsTer13). Under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1, consistent with BRCA1 loss of function as an established disease mechanism.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the ENIGMA BRCA1 PM2 threshold for absence from population controls.
PM5Strong
PM5 · strong
This protein-truncating variant occurs in BRCA1 exon 10 (legacy exon 11), an exon designated PM5_Strong (PTC) in the ENIGMA BRCA1 exon table, indicating that different proven pathogenic protein-truncating variants have been observed in this exon.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework via CSPEC/VCEP override for final criteria combinations.
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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
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: 3 met · 2 not met · 9 not assessed · 14 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.2063del (p.Thr688LysfsTer13; p.T688Kfs*13) variant has not been observed in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population controls.
This frameshift deletion occurs in BRCA1 exon 10 (legacy exon 11) and is predicted to introduce a premature termination codon; under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1 and the exon also carries PM5_Strong (PTC).
SpliceAI predicts no significant additional splice impact for this deletion, with a maximum delta score of 0.00.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a frameshift deletion in BRCA1 exon 10 (legacy exon 11) predicted to cause p.(Thr688LysfsTer13). Under the ENIGMA BRCA1 specification, truncating variants in this exon meet PVS1, consistent with BRCA1 loss of function as an established disease mechanism. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 for truncating variant in exon 10(11)
Evidence considered
- NM_007294.4:c.2063del normalizes to p.(Thr688LysfsTer13) / p.(T688Kfs*13)
- Variant maps to BRCA1 exon 10
- ENIGMA Table 4 assigns exon 10(11) truncating variants to PVS1
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the ENIGMA BRCA1 PM2 threshold for absence from population controls. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2_Supporting for absence from controls
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PM5 StrongThis protein-truncating variant occurs in BRCA1 exon 10 (legacy exon 11), an exon designated PM5_Strong (PTC) in the ENIGMA BRCA1 exon table, indicating that different proven pathogenic protein-truncating variants have been observed in this exon. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5_Strong (PTC) for exon 10(11)
Evidence considered
- Variant is a protein-truncating frameshift
- ENIGMA Table 4 assigns exon 10(11) PM5_Strong (PTC)
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the BA1 population threshold. Details ▾Hide ▴
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 and therefore does not exceed the BS1 population frequency thresholds. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
Not assessed · 9 · no assessment recorded
PS3 No variant-specific calibrated functional study result was identified for this frameshift variant in the curated ENIGMA functional assay resources, so PS3 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed ENIGMA functional assay resources for exact variant evidence
Still missing
- No directly curated protein or combined mRNA/protein functional assay result for this exact variant was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS4 No case-control study or quantified enrichment data were identified for this exact variant, so PS4 cannot be applied. Details ▾Hide ▴
Evidence considered
- No verified case-control dataset for this exact variant was identified
Still missing
- Affected versus control counts for this exact variant were not identified.
PM3 No data were identified showing this variant in trans with another BRCA1 variant in an individual with BRCA1-related Fanconi anemia, so PM3 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed PM3 framework requirements
Still missing
- No qualifying recessive disease or trans-phase evidence was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Evidence considered
- No verified segregation evidence for exact variant
Still missing
- No informative family cosegregation data were identified.
PP4 No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so PP4 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed BRCA1 clinical-history LR resource for exact HGVS match
Still missing
- No qualifying multifactorial clinical-history LR for this exact variant was identified.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
BS2 No qualifying observations in individuals lacking features of BRCA1-related Fanconi anemia were identified for this variant, so BS2 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed BS2 framework requirements
Still missing
- No point-scored BS2 observations were identified.
Sources
BS3 No variant-specific calibrated functional study showing no damaging effect was identified for this frameshift variant in the curated ENIGMA functional assay resources, so BS3 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed ENIGMA functional assay resources for exact variant evidence
Still missing
- No directly curated benign functional assay result for this exact variant was identified.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BS4 No non-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Evidence considered
- No verified non-segregation evidence for exact variant
Still missing
- No informative lack-of-segregation evidence was identified.
BP5 No variant-level clinical-history likelihood ratio entry was identified for this exact variant in the BRCA1 ENIGMA clinical-history resource, so BP5 was not applied. Details ▾Hide ▴
Evidence considered
- Reviewed BRCA1 clinical-history LR resource for exact HGVS match
Still missing
- No qualifying multifactorial clinical-history LR against pathogenicity was identified for this exact variant.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a frameshift deletion, not a missense variant and not an alternate nucleotide change with the same defined splicing effect as a previously classified pathogenic variant, so PS1 does not apply. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS2 VCEPThe ENIGMA BRCA1 specification lists PS2 as not applicable in this framework. Details ▾Hide ▴
PM1 VCEPPM1 is not used for this frameshift variant in the BRCA1 ENIGMA framework, which applies domain-based PM1 logic to specific missense contexts rather than truncating variants. Details ▾Hide ▴
PM4 VCEPThe ENIGMA BRCA1 specification lists PM4 as not applicable in this framework. Details ▾Hide ▴
PM6 VCEPThe ENIGMA BRCA1 specification lists PM6 as not applicable in this framework. Details ▾Hide ▴
PP2 VCEPThe ENIGMA BRCA1 specification lists PP2 as not applicable in this framework. Details ▾Hide ▴
PP3 N/APP3 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants with predicted damaging protein or splicing effects. This variant is a frameshift deletion, so PP3 does not apply. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
PP5 VCEPThe ENIGMA BRCA1 specification lists PP5 as not applicable in this framework. Details ▾Hide ▴
BP1 N/ABP1 in the ENIGMA BRCA1 framework is used for qualifying silent, missense, or in-frame variants outside clinically important domains without predicted splicing impact. This frameshift deletion does not fit that rule. Details ▾Hide ▴
BP2 VCEPThe ENIGMA BRCA1 specification lists BP2 as not applicable in this framework. Details ▾Hide ▴
BP3 VCEPThe ENIGMA BRCA1 specification lists BP3 as not applicable in this framework. Details ▾Hide ▴
BP4 N/ABP4 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants without predicted impact. This variant is a frameshift deletion, so BP4 does not apply. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
BP6 VCEPThe ENIGMA BRCA1 specification lists BP6 as not applicable in this framework. Details ▾Hide ▴
BP7 N/ABP7 in the ENIGMA BRCA1 framework is used for qualifying silent or intronic variants, and in limited RNA-specific situations for other variant classes. This frameshift deletion does not meet those use conditions. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.2063del
- Protein (HGVS p.)
- NP_009225.1:p.(Thr688LysfsTer13)
- GRCh38
- chr17:43093467 TG>T
- GRCh37
- chr17:41245484 TG>T
- ClinVar
- 3638588, 821496, 266258, 266244
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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants with predicted damaging protein or splicing effects. This variant is a frameshift deletion, so PP3 does not apply. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
BP4 N/ABP4 in the ENIGMA BRCA1 framework is used for qualifying missense, in-frame, silent, or intronic variants without predicted impact. This variant is a frameshift deletion, so BP4 does not apply. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
BP7 N/ABP7 in the ENIGMA BRCA1 framework is used for qualifying silent or intronic variants, and in limited RNA-specific situations for other variant classes. This frameshift deletion does not meet those use conditions. Details ▾Hide ▴
Evidence considered
- Variant consequence is frameshift
- SpliceAI max delta score 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
8 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 11358863 ↗Tumorigenesis in mice carrying a truncating Brca1 mutation.No paper-specific finding is recorded.
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PMID 12483515 ↗The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.No paper-specific finding is recorded.
-
PMID 12947386 ↗Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.No paper-specific finding is recorded.
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PMID 20608970 ↗BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.No paper-specific finding is recorded.
-
PMID 20104584 ↗Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.Borg A et al. · 2010No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No 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.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.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
Captured ClinVar source record
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/?term=NM_007294.4%3Ac.2063del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41245484-TG-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43093467-TG-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.2063…
- OncoKB ↗www.oncokb.org/gene/BRCA1/T688Kfs*13
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.2063del
- 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.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.