About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.5089T>C, p.(Cys1697Arg)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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
PS3Strong
PS3 · strong
Calibrated BRCA1 functional studies show this variant has damaging loss-of-function effects. ENIGMA Table 9 assigns PS3_Strong to c.5089T>C based on three studies, and supplementary functional tables classify p.(Cys1697Arg) as having complete functional impact/loss of function.
PP3Supporting
PP3 · supporting
This missense variant is located in the BRCA1 BRCT repeats (amino acids 1650-1857), has a BayesDel score of 0.398, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08. These findings support a damaging protein effect consistent with PP3.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/Table 3 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.
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.
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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 · 7 not met · 7 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.5089T>C (p.Cys1697Arg) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and is listed in OncoKB as Likely Oncogenic with loss-of-function effect.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
Calibrated BRCA1 functional studies compiled by ENIGMA show complete functional impact/loss of function for p.(Cys1697Arg), supporting PS3_Strong.
The variant lies within the BRCA1 BRCT repeat region, has a BayesDel score of 0.398 which is above the PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08, supporting PP3.
No criteria match.
Met · 3
PS3 StrongCalibrated BRCA1 functional studies show this variant has damaging loss-of-function effects. ENIGMA Table 9 assigns PS3_Strong to c.5089T>C based on three studies, and supplementary functional tables classify p.(Cys1697Arg) as having complete functional impact/loss of function. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS3 Strong for calibrated functional evidence showing damaging effect.
Evidence considered
- ENIGMA Table 9 lists BRCA1 c.5089T>C p.(Cys1697Arg) as PS3 Strong.
- Table 9 cites three calibrated studies: Findlay 2018
- Petitalot 2019
- and Fernandes 2019.
- Supplementary Table 4 records Functional impact - complete and LOF for c.5089T>C.
- HUMU supplementary data show posterior probability 0.99986659028339631 and functional impact consistent with pathogenicity.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
PP3 SupportingThis missense variant is located in the BRCA1 BRCT repeats (amino acids 1650-1857), has a BayesDel score of 0.398, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08. These findings support a damaging protein effect consistent with PP3. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 Supporting for missense variants in a clinically important domain with BayesDel ≥0.28.
Evidence considered
- Variant protein position is Cys1697 within the BRCT repeats.
- Supplementary bioinformatic data show BayesDel 0.39813199999999999.
- ENIGMA PP3 threshold for missense variants in clinically important domains is BayesDel ≥0.28.
- SpliceAI max delta score is 0.08
- below the splicing-prediction threshold for PP3 splicing use.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PP4 The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08, so PP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP4 requires LR ≥2.08 for Supporting strength.
Evidence considered
- Clinical-history workbook row: BRCA1 c.5089T>C.
- LOG(LR)=0.1919582486152649.
- LR=1.211619929099039.
- N_Probands=1.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the BA1 threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BA1 requires FAF >0.001.
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 meet the BS1 thresholds of filter allele frequency above 0.002% or 0.01%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS1 requires elevated population frequency.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS3 Available calibrated functional studies do not show a neutral effect. Instead, ENIGMA Table 9 and the supplementary functional dataset classify this variant as damaging with complete functional impact/loss of function, so BS3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS3 requires calibrated functional evidence showing no damaging effect.
Evidence considered
- Table 9 assigns PS3 Strong
- not BS3.
- Supplementary Table 4 lists Functional impact - complete and LOF for c.5089T>C.
Sources
BP1 This missense variant is located within the BRCA1 BRCT repeats rather than outside a clinically important domain, and the BayesDel score is 0.398, which does not support a benign protein prediction. Therefore BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP1_Strong requires a missense variant outside a clinically important domain and no predicted splicing effect.
Evidence considered
- BRCT repeats are defined as amino acids 1650-1857.
- Cys1697 lies within the BRCT repeats.
- BayesDel score is 0.39813199999999999.
- SpliceAI max delta score is 0.08.
Sources
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, the BayesDel score is 0.398, which is above the benign threshold of 0.15. Because BP4 for missense variants in clinically important domains requires BayesDel ≤0.15 and SpliceAI ≤0.1, BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 Supporting requires benign computational evidence in the specified context.
Evidence considered
- Variant lies in the BRCT repeats.
- BayesDel score is 0.39813199999999999.
- BP4 benign threshold is BayesDel ≤0.15.
- SpliceAI max delta score is 0.08
- which is ≤0.1.
Sources
BP5 The BRCA1 clinical-history likelihood ratio for this variant is 1.21 in 1 proband, which is above the ENIGMA BP5 threshold of 0.48 and falls in the neutral zone, so BP5 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP5 requires LR ≤0.48 for Supporting strength.
Evidence considered
- Clinical-history workbook row: BRCA1 c.5089T>C.
- LOG(LR)=0.1919582486152649.
- LR=1.211619929099039.
- N_Probands=1.
Sources
Not assessed · 7 · no assessment recorded
PS1 No previously classified pathogenic variant with the same amino acid substitution was identified in the reviewed evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PS1 requires the same amino acid substitution or same predicted splicing effect as a previously classified pathogenic reference variant.
Evidence considered
- ClinVar reports this specific variant but the reviewed materials did not identify a different nucleotide change producing the same amino acid substitution with established pathogenic classification.
Still missing
- A dedicated same-amino-acid match review in the ENIGMA PS1 reference set would be needed for full exclusion.
Sources
PS4 The reviewed evidence does not provide a case-control analysis with p-value ≤0.05 and odds ratio ≥4 with the lower confidence interval excluding 2.0, so PS4 was not applied. Details ▾Hide ▴
PM2 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is consistent with rarity, but the ENIGMA PM2 rule specifically requires absence in gnomAD v2.1 and v3.1 with average read depth ≥25, and those full coverage elements were not provided here. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM2_Supporting requires absence from gnomAD v2.1 and v3.1 with average read depth ≥25.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Still missing
- gnomAD v3.1 absence was not directly provided.
- Average read depth for the region was not provided.
Sources
PM3 No evidence was identified for biallelic BRCA1 disease or Fanconi anemia probands with qualifying co-occurring BRCA1 variants, so PM3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM3 is reserved for qualifying BRCA1/2-related Fanconi anemia cases.
Evidence considered
- The reviewed evidence does not include BRCA1-related Fanconi anemia observations for this variant.
Still missing
- No qualifying recessive-disease proband data were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP1 requires quantitative co-segregation evidence.
Evidence considered
- The reviewed materials did not include a quantitative segregation analysis for c.5089T>C.
Still missing
- No family segregation likelihood ratio was provided.
Sources
BS2 No qualifying point-based evidence was identified from individuals without Fanconi anemia features, so BS2 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS2 requires qualifying point-based evidence in the absence of recessive disease features.
Evidence considered
- The reviewed materials do not provide ENIGMA Table 8 point assignments for BS2.
Still missing
- No qualifying BS2 proband data were identified.
Sources
BS4 No quantitative evidence for lack of segregation was identified, so BS4 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BS4 requires quantitative lack-of-segregation evidence.
Evidence considered
- The reviewed evidence does not include a BS4-qualifying segregation analysis.
Still missing
- No segregation likelihood ratio showing lack of segregation was provided.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a null variant or canonical ±1/2 splice variant, so the BRCA1 ENIGMA PVS1 rule does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PVS1 applies to null variants or qualifying RNA evidence, not to this missense substitution.
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the ENIGMA framework.
- NM_007294.4:c.5089T>C is a missense change encoding p.(Cys1697Arg)
- outside the generic PVS1 null-variant buckets.
Sources
PS2 N/ADe novo evidence is not used for BRCA1 in this specification, so PS2 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: PS2 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks PS2 as not applicable.
Sources
PM1 N/AAlthough this variant lies in the BRCA1 BRCT region, PM1 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: PM1 not applicable.
Evidence considered
- The BRCT repeats are defined as BRCA1 amino acids 1650-1857.
- ENIGMA BRCA1 v1.2 marks PM1 as not applicable.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18
PM4 N/APM4 does not apply because this is not a protein length-changing variant, and the BRCA1 ENIGMA specification marks PM4 as not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: PM4 not applicable.
Evidence considered
- This variant is a missense substitution.
- ENIGMA BRCA1 v1.2 marks PM4 as not applicable.
Sources
PM5 N/AIn the BRCA1 ENIGMA specification, PM5 is used for protein-terminating variants in eligible exons. This variant is missense, so PM5 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PM5 is limited to qualifying PTC variants.
Evidence considered
- ENIGMA BRCA1 PM5 is specified as PM5_PTC for protein-terminating variants.
- NM_007294.4:c.5089T>C is a missense substitution.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AAssumed de novo evidence is not used for BRCA1 in this specification, so PM6 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: PM6 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks PM6 as not applicable.
Sources
PP2 N/APP2 is not used in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: PP2 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks PP2 as not applicable.
Sources
BP2 N/ABP2 is not used in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: BP2 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: BP3 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks BP3 as not applicable.
Sources
BP6 N/ABP6 is not used in the BRCA1 ENIGMA specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2: BP6 not applicable.
Evidence considered
- ENIGMA BRCA1 v1.2 marks BP6 as not applicable.
Sources
BP7 N/AThis is a missense variant rather than a silent or intronic variant in the ENIGMA BP7 categories, so BP7 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7 applies to specific silent, intronic, or RNA-only functional contexts.
Evidence considered
- NM_007294.4:c.5089T>C causes p.(Cys1697Arg).
- SpliceAI max delta score is 0.08.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.5089T>C
- Protein (HGVS p.)
- NP_009225.1:p.(Cys1697Arg)
- GRCh38
- chr17:43063937 A>G
- GRCh37
- chr17:41215954 A>G
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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingThis missense variant is located in the BRCA1 BRCT repeats (amino acids 1650-1857), has a BayesDel score of 0.398, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.08. These findings support a damaging protein effect consistent with PP3. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 PP3 Supporting for missense variants in a clinically important domain with BayesDel ≥0.28.
Evidence considered
- Variant protein position is Cys1697 within the BRCT repeats.
- Supplementary bioinformatic data show BayesDel 0.39813199999999999.
- ENIGMA PP3 threshold for missense variants in clinically important domains is BayesDel ≥0.28.
- SpliceAI max delta score is 0.08
- below the splicing-prediction threshold for PP3 splicing use.
Sources
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.08, the BayesDel score is 0.398, which is above the benign threshold of 0.15. Because BP4 for missense variants in clinically important domains requires BayesDel ≤0.15 and SpliceAI ≤0.1, BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP4 Supporting requires benign computational evidence in the specified context.
Evidence considered
- Variant lies in the BRCT repeats.
- BayesDel score is 0.39813199999999999.
- BP4 benign threshold is BayesDel ≤0.15.
- SpliceAI max delta score is 0.08
- which is ≤0.1.
Sources
BP7 N/AThis is a missense variant rather than a silent or intronic variant in the ENIGMA BP7 categories, so BP7 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 v1.2 BP7 applies to specific silent, intronic, or RNA-only functional contexts.
Evidence considered
- NM_007294.4:c.5089T>C causes p.(Cys1697Arg).
- SpliceAI max delta score is 0.08.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
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 ↗
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/55392/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41215954-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43063937-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.5089…
- OncoKB ↗www.oncokb.org/gene/BRCA1/C1697R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.5089T%3EC
- 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 Likely pathogenic (6 clinical laboratories) and as Pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Loss-of-function.
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.