About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.615_622dup, p.(Thr208AsnfsTer29)
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: 0
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
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 final-classification framework (ACMG/AMP 2015 with ENIGMA Table 3 adaptations)
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.
No listed criterion applied
SpliceAI score
0.110 maximum delta
Recorded SpliceAI maximum delta score: 0.110. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance.
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: 0 met · 2 not met · 8 not assessed · 18 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.615_622dup (p.Thr208AsnfsTer29; p.T208Nfs*29) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as uncertain significance.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the available documentation was insufficient to assign BRCA1 ENIGMA PM2_Supporting under the full dataset and coverage requirements.
Under the ENIGMA BRCA1 specification, this frameshift lies in exon 9(10), an exon designated PVS1_N/A and PM5_N/A for protein-truncating variants because rescue of an in-frame transcript is expected, so truncating status alone does not support PVS1 or PM5.
SpliceAI shows a maximum delta score of 0.11, which is below the BRCA1 splice PP3 threshold of 0.20 and above the BP4 no-impact threshold of 0.10; however, the BRCA1 computational rules are not designed to add PP3 or BP4 evidence for this frameshift variant.
No criteria match.
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 BRCA1 ENIGMA BA1 frequency threshold. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BA1 rule
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 meet the BRCA1 ENIGMA BS1 frequency thresholds. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS1 rule
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not assessed · 8 · no assessment recorded
PS4 This variant has been reported in ClinVar, but no case-control data were identified showing a significant enrichment in affected individuals with p-value 0.05 or less and odds ratio 4 or greater. Available evidence does not support PS4 at this time. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS4 rule
Evidence considered
- ClinVar contains a record for this variant.
- The BRCA1 PS4 rule requires significant case-control enrichment.
Still missing
- No validated case-control dataset with odds ratio and confidence interval was identified.
- No quantitative prevalence comparison against controls was identified.
Sources
PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity. However, the BRCA1 ENIGMA PM2 rule requires absence in the specified control datasets together with adequate regional coverage, and those coverage requirements were not documented here, so PM2_Supporting was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM2 rule
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Still missing
- The required coverage confirmation for the locus was not documented.
- The rule text references the specified ENIGMA control datasets
- and direct confirmation under that exact rule set was not available here.
Sources
PM3 PM3 in the BRCA1 ENIGMA specification is reserved for BRCA1- or BRCA2-related Fanconi anemia with qualifying trans observations and point-based evidence. No such recessive-disease or trans-phase evidence was identified for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM3 rule
Evidence considered
- PM3 is phenotype- and phase-dependent in the BRCA1 specification.
Still missing
- No Fanconi anemia phenotype data were identified.
- No confirmed trans observation with another pathogenic BRCA1 variant was identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant. Available evidence does not provide a segregation likelihood ratio meeting BRCA1 ENIGMA PP1 thresholds. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP1 rule
Evidence considered
- ClinVar reporting does not provide a quantitative segregation LR here.
- The BRCA1 PP1 rule requires a quantitative co-segregation analysis.
Still missing
- No pedigree-based segregation likelihood ratio was identified.
- No validated meiosis count or segregation analysis was identified.
Sources
PP4 No variant-level clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials. Therefore, PP4 was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP4 rule
Evidence considered
- The BRCA1 ENIGMA framework uses clinical-history likelihood ratios for PP4/BP5.
- No exact workbook match for this HGVS was identified.
Still missing
- No exact match for c.615_622dup was identified in the BRCA1 clinical-history LR workbook.
- No qualifying combined likelihood ratio of 2.08 or greater was documented.
Sources
BS2 BS2 in the BRCA1 ENIGMA framework requires point-based evidence from individuals without features of recessive disease, specifically Fanconi anemia. No such proband-level evidence was identified for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS2 rule
Evidence considered
- BS2 is phenotype-dependent in the BRCA1 specification.
Still missing
- No phenotype-negative proband data relevant to BRCA1-related Fanconi anemia were identified.
- No BS2 point-based evidence was identified.
Sources
BS4 No quantitative lack-of-segregation evidence was identified for this variant. Available evidence does not provide a segregation likelihood ratio low enough to support BS4. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS4 rule
Evidence considered
- The BRCA1 BS4 rule requires a quantitative non-segregation analysis.
Still missing
- No pedigree-based non-segregation likelihood ratio was identified.
- No validated unaffected-carrier or contradictory segregation dataset was identified.
Sources
BP5 No variant-level clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant in the reviewed BRCA1 clinical-history materials. Therefore, BP5 was not assigned. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP5 rule
Evidence considered
- The BRCA1 ENIGMA framework uses clinical-history likelihood ratios for PP4/BP5.
- No exact workbook match for this HGVS was identified.
Still missing
- No exact match for c.615_622dup was identified in the BRCA1 clinical-history LR workbook.
- No qualifying combined likelihood ratio of 0.48 or less was documented.
Sources
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a frameshift change, but the ENIGMA BRCA1 specification designates protein-truncating variants in exon 9(10) as PVS1_N/A because rescue of an in-frame transcript is expected in this region. Therefore, the truncating consequence alone does not support PVS1 for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 exon-specific PVS1 rule
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the gene-specific framework.
- The variant is predicted as p.(Thr208AsnfsTer29) / p.(T208Nfs*29).
- ENIGMA Table 4 marks exon 9(10) PTC variants as PVS1_N/A.
Sources
PS1 N/APS1 is used for the same amino-acid change as a previously established pathogenic variant, or for the same predicted splicing effect as a known pathogenic variant. This frameshift duplication does not match that evidence model. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS1 rule
Evidence considered
- The variant is a frameshift duplication rather than a same-amino-acid substitution.
Sources
PS2 VCEPThe BRCA1 ENIGMA specification does not use PS2 for this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PS2 is listed as not applicable in the BRCA1 specification.
Sources
PS3 N/AThe BRCA1 ENIGMA PS3 framework uses calibrated functional evidence for specific missense or synonymous variants. No calibrated protein-based functional result was identified for this frameshift duplication, and the available functional tables are not designed to assign PS3 to this variant type. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS3/Table 9 rule
Evidence considered
- Table 9 is the curated BRCA1 functional assay source for PS3/BS3.
- No exact match for c.615_622dup was identified in the reviewed functional materials.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PM1 VCEPThe BRCA1 ENIGMA specification lists PM1 as not applicable in this framework, and this variant is a truncating duplication rather than a missense change evaluated by domain-based PM1 rules. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PM1 is marked not applicable in the BRCA1 specification.
Sources
PM4 VCEPThe BRCA1 ENIGMA specification does not use PM4 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PM4 is listed as not applicable in the BRCA1 specification.
Sources
PM5 N/AFor BRCA1, PM5 is repurposed for protein-truncating variants rather than classic same-residue missense logic. This variant is in exon 9(10), and ENIGMA Table 4 designates protein-truncating variants in this exon as PM5_N/A, so PM5 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM5_PTC exon-specific rule
Evidence considered
- PM5 candidate harvesting identified that BRCA1 uses a PTC-specific PM5 framework here.
- ENIGMA Table 4 marks exon 9(10) PTC variants as PM5_N/A.
Sources
PM6 VCEPThe BRCA1 ENIGMA specification does not use PM6 for this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PM6 is listed as not applicable in the BRCA1 specification.
Sources
PP2 VCEPThe BRCA1 ENIGMA specification does not use PP2 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PP2 is listed as not applicable in the BRCA1 specification.
Sources
PP3 N/ABRCA1 ENIGMA PP3 applies to missense or in-frame variants in defined functional domains with BayesDel support, or to variants with predicted splice impact when SpliceAI is 0.20 or greater. This variant is a frameshift duplication, and SpliceAI shows a maximum delta score of 0.11, below the splice PP3 threshold, so PP3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 rule
Evidence considered
- SpliceAI max delta score = 0.11.
- REVEL and BayesDel were not available because this is not an SNV.
Sources
PP5 VCEPThe BRCA1 ENIGMA specification does not use PP5 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- PP5 is listed as not applicable in the BRCA1 specification.
Sources
BS3 N/AThe BRCA1 ENIGMA BS3 framework uses calibrated functional evidence for specific missense or synonymous variants. No calibrated functional evidence showing no damaging effect was identified for this frameshift duplication. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS3/Table 9 rule
Evidence considered
- Table 9 is the curated BRCA1 functional assay source for PS3/BS3.
- No exact match for c.615_622dup was identified in the reviewed functional materials.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
BP1 N/ABP1_Strong in the BRCA1 ENIGMA specification is used for silent, missense, or in-frame variants outside defined functional domains with no predicted splice effect. This frameshift duplication does not match that evidence model. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP1 rule
Evidence considered
- BP1 is limited to non-truncating variant classes in the BRCA1 specification.
Sources
BP2 VCEPThe BRCA1 ENIGMA specification does not use BP2 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- BP2 is listed as not applicable in the BRCA1 specification.
Sources
BP3 VCEPThe BRCA1 ENIGMA specification does not use BP3 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- BP3 is listed as not applicable in the BRCA1 specification.
Sources
BP4 N/ABRCA1 ENIGMA BP4 applies to selected missense, in-frame, silent, or intronic variants with no predicted splice impact, including SpliceAI 0.10 or less in the relevant contexts. This variant is a frameshift duplication, and SpliceAI is 0.11, so BP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 rule
Evidence considered
- SpliceAI max delta score = 0.11.
- The variant class is frameshift rather than a BP4-eligible variant type.
Sources
BP6 VCEPThe BRCA1 ENIGMA specification does not use BP6 in this framework. Details ▾Hide ▴
VCEP rule
ENIGMA BRCA1 v1.2 applicability table
Evidence considered
- BP6 is listed as not applicable in the BRCA1 specification.
Sources
BP7 N/ABRCA1 ENIGMA BP7 is used for silent or intronic variants with evidence against splice disruption, or for RNA evidence showing no damaging transcript effect in eligible variant classes. This frameshift duplication does not match that evidence model. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7 rule
Evidence considered
- The variant class is frameshift.
- SpliceAI max delta score = 0.11
- but BP7 is not defined for frameshift duplications.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.615_622dup
- Protein (HGVS p.)
- NP_009225.1:p.(Thr208AsnfsTer29)
- GRCh38
- chr17:43095893 G>GTGATTTGT
- GRCh37
- chr17:41247910 G>GTGATTTGT
- ClinVar
- 926510
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
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/ABRCA1 ENIGMA PP3 applies to missense or in-frame variants in defined functional domains with BayesDel support, or to variants with predicted splice impact when SpliceAI is 0.20 or greater. This variant is a frameshift duplication, and SpliceAI shows a maximum delta score of 0.11, below the splice PP3 threshold, so PP3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 rule
Evidence considered
- SpliceAI max delta score = 0.11.
- REVEL and BayesDel were not available because this is not an SNV.
Sources
BP4 N/ABRCA1 ENIGMA BP4 applies to selected missense, in-frame, silent, or intronic variants with no predicted splice impact, including SpliceAI 0.10 or less in the relevant contexts. This variant is a frameshift duplication, and SpliceAI is 0.11, so BP4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 rule
Evidence considered
- SpliceAI max delta score = 0.11.
- The variant class is frameshift rather than a BP4-eligible variant type.
Sources
BP7 N/ABRCA1 ENIGMA BP7 is used for silent or intronic variants with evidence against splice disruption, or for RNA evidence showing no damaging transcript effect in eligible variant classes. This frameshift duplication does not match that evidence model. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7 rule
Evidence considered
- The variant class is frameshift.
- SpliceAI max delta score = 0.11
- but BP7 is not defined for frameshift duplications.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
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
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PMID 11358863 ↗Tumorigenesis in mice carrying a truncating Brca1 mutation.No paper-specific finding is recorded.
-
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.
-
PMID 20608970 ↗BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.No paper-specific finding is recorded.
-
PMID 12203997 ↗Analysis of breast cancer susceptibility genes BRCA1 and BRCA2 in Thai familial and isolated early-onset breast and ovarian cancer.Patmasiriwat P et al. · 2002No paper-specific finding is recorded.
-
PMID 16211554 ↗Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families.Tesoriero AA et al. · 2005No paper-specific finding is recorded.
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PMID 19892845 ↗Alternative splicing and molecular characterization of splice site variants: BRCA1 c.591C>T as a case study.Dosil V et al. · 2010No paper-specific finding is recorded.
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PMID 20104584 ↗Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.No 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 0.110
Open source ↗
ClinVar
3 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/926510/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41247910-G-GTGATTTGT?datas…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43095893-G-GTGATTTGT?da…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.615_…
- OncoKB ↗www.oncokb.org/gene/BRCA1/T208Nfs*29
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.615_622dup
- 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 has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 926510)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.11).
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.