About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.191G>A, p.(Cys64Tyr)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
ENIGMA BRCA1 Table 9 assigns PS3 Strong for this variant because a calibrated functional study reported protein function similar to pathogenic control variants, and supplementary functional datasets classify the variant as having complete functional impact or loss of function.
PP3Supporting
PP3 · supporting
This missense variant is located in the BRCA1 RING domain, and the reviewed bioinformatic evidence supports a deleterious effect: BayesDel no-AF is 0.557106, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts splice impact with a maximum delta score of 0.87, which is above the splice threshold of 0.2.
PP4Strong
PP4 · strong
BRCA1 clinical-history likelihood-ratio data show an LR of 69.10003048643809 across 9 probands for this variant, which is above the ENIGMA PP4 Strong threshold of 18.7 and supports pathogenicity.
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: Pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification framework (criteria combination)
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
2 / 1,601,934 alleles
gnomAD v4.1: 2 / 1,601,934 alleles. Recorded AF 1.24849e-06. Recorded homozygote count 0.
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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
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: 4 met · 8 not met · 6 not assessed · 10 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.191G>A (p.Cys64Tyr) variant has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA expert panel and by multiple clinical laboratories.
This variant is absent from gnomAD v2.1 and is present at an extremely low frequency in gnomAD v4.1 (2/1,601,934 alleles; AF 1.24849e-06; highest observed subpopulation AF 1.61181e-05).
ENIGMA BRCA1 functional evidence assigns PS3 Strong for this variant, and supplementary functional datasets classify it as having complete functional impact or loss of function.
BRCA1 clinical-history likelihood-ratio data show LR 69.1 across 9 probands for this variant, exceeding the PP4 Strong threshold of 18.7.
The variant lies in the BRCA1 RING domain and is predicted to be damaging by BayesDel no-AF 0.557106, which is above the ENIGMA PP3 threshold of 0.28; SpliceAI also predicts splice impact with a maximum delta score of 0.87.
No criteria match.
Met · 4
PS3 StrongENIGMA BRCA1 Table 9 assigns PS3 Strong for this variant because a calibrated functional study reported protein function similar to pathogenic control variants, and supplementary functional datasets classify the variant as having complete functional impact or loss of function. Details ▾Hide ▴
Rule
ENIGMA BRCA1 Table 9 calibrated protein functional evidence
Evidence considered
- Table 9 entry: BRCA1 c.191G>A p.(Cys64Tyr) -> PS3 Strong
- ST4: Functional impact - complete / LOF
- SuppT4: functional assay data support complete impact
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:30209399 ↗
PP3 SupportingThis missense variant is located in the BRCA1 RING domain, and the reviewed bioinformatic evidence supports a deleterious effect: BayesDel no-AF is 0.557106, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts splice impact with a maximum delta score of 0.87, which is above the splice threshold of 0.2. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for damaging BayesDel and/or predicted splice impact
Evidence considered
- RING domain location
- BayesDel noAF 0.557106
- SpliceAI max delta 0.87
Sources
PP4 StrongBRCA1 clinical-history likelihood-ratio data show an LR of 69.10003048643809 across 9 probands for this variant, which is above the ENIGMA PP4 Strong threshold of 18.7 and supports pathogenicity. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 likelihood-ratio thresholds
Evidence considered
- clinical-history LR 69.10003048643809
- N probands 9
- PP4 Strong threshold 18.7
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴
Not met · 8 · evaluated, threshold not reached
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at a very low frequency (2/1,601,934 alleles; AF 1.24849e-06; highest observed subpopulation AF 1.61181e-05), so the strict absence-from-controls requirement for PM2 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2 requires absence from controls
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AC 2/AN 1601934
- gnomAD v4.1 total AF 1.248490886640773e-06
Sources
BA1 The variant frequency is well below the BA1 threshold of 0.001. In gnomAD v4.1 the total AF is 1.24849e-06 and the highest observed subpopulation AF is 1.61181e-05, so BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 frequency threshold
Evidence considered
- gnomAD v4.1 total AF 1.248490886640773e-06
- highest subpopulation AF 1.611811353599175e-05
- BA1 threshold 0.001
Sources
BS1 The variant frequency is below both BS1 thresholds. The highest observed subpopulation AF in gnomAD v4.1 is 1.61181e-05, which is below 0.00002 for BS1 Supporting and below 0.0001 for BS1 Strong, so BS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 frequency thresholds
Evidence considered
- highest subpopulation AF 1.611811353599175e-05
- BS1 Supporting threshold 0.00002
- BS1 Strong threshold 0.0001
Sources
BS3 Although mRNA studies reported no aberration, the calibrated ENIGMA BRCA1 functional summary for this variant assigns PS3 Strong and the supplementary functional datasets classify the variant as complete functional impact or loss of function, so benign functional evidence is not supported. Details ▾Hide ▴
Rule
BS3 requires well-established evidence of no damaging effect
Evidence considered
- Table 9 assigns PS3 Strong
- ST4: Functional impact - complete / LOF
- mRNA note: no aberration in 2 studies
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗PMID:22505045 ↗PMID:32741062 ↗
BP1 This missense variant is located in the BRCA1 RING domain, which is a clinically important functional domain, and the predictive evidence does not show no-splicing-impact because SpliceAI is 0.87, above the <=0.1 threshold; therefore BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong rule
Evidence considered
- RING domain location
- SpliceAI max delta 0.87
- BP1 requires location outside clinically important domain and SpliceAI <=0.1
Sources
BP4 This missense variant is in the BRCA1 RING domain, but the predictive evidence does not support a benign effect: BayesDel no-AF is 0.557106, which is above the BP4 benign threshold of <=0.15, and SpliceAI is 0.87, which is above the <=0.1 threshold. BP4 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 rule
Evidence considered
- BayesDel noAF 0.557106
- SpliceAI max delta 0.87
- BP4 thresholds: BayesDel <=0.15 and SpliceAI <=0.1
Sources
BP5 The clinical-history likelihood ratio for this variant is 69.10003048643809 in the pathogenic direction, which is well above the benign BP5 thresholds of <=0.48, <=0.23, and <=0.05, so BP5 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP5 likelihood-ratio thresholds
Evidence considered
- clinical-history LR 69.10003048643809
- BP5 thresholds <=0.48
- <=0.23
- <=0.05
Sources
BP7 mRNA studies reported no aberration, but this missense variant lies within the BRCA1 RING domain and ENIGMA requires BS3 for BP7_Strong RNA in this setting; because BS3 is not supported and the functional evidence supports damage, BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 RNA rule for missense variants in functional domains
Evidence considered
- RING domain location
- mRNA note: no aberration in 2 studies
- BS3 not supported
Sources
Not assessed · 6 · no assessment recorded
PS1 No evidence was identified here showing that a different nucleotide change causing the same amino acid substitution or the same splicing outcome has already been classified as pathogenic or likely pathogenic under the ENIGMA BRCA1 rules. Details ▾Hide ▴
Rule
PS1 requires the same protein change or same predicted splice effect as a previously classified pathogenic or likely pathogenic variant
Evidence considered
- missense variant in BRCA1
- no matched PS1 reference variant identified in reviewed materials
Still missing
- A same-amino-acid or same-splice reference variant classified under the ENIGMA BRCA1 framework was not documented.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PS4 This variant has been reported in affected individuals, but no case-control analysis with p-value <=0.05 and odds ratio >=4 with the lower confidence interval excluding 2.0 was identified here, so PS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires qualifying case-control evidence
Evidence considered
- ClinVar pathogenic reporting
- no qualifying ENIGMA PS4 case-control dataset identified
Still missing
- No qualifying case-control statistics were identified.
Sources
PM3 No evidence was identified for biallelic BRCA1 disease with a Fanconi-anemia-consistent phenotype and an ENIGMA point assignment for this variant, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 requires Fanconi-anemia-related biallelic evidence
Evidence considered
- no PM3-specific proband evidence identified
Still missing
- No qualifying recessive-disease proband data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP1 No quantitative co-segregation analysis meeting ENIGMA thresholds was identified, so PP1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP1 requires a quantitative segregation likelihood ratio
Evidence considered
- no qualifying segregation likelihood ratio identified
Still missing
- No family-based likelihood ratio meeting PP1 thresholds was documented.
Sources
BS2 No ENIGMA point-based evidence from unaffected individuals without Fanconi anemia features was identified for this variant, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 requires point-based evidence from unaffected individuals
Evidence considered
- no BS2-specific proband evidence identified
Still missing
- No BS2 point-assignment data were identified.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BS4 No quantitative lack-of-segregation analysis meeting ENIGMA BS4 thresholds was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS4 requires a quantitative non-segregation likelihood ratio
Evidence considered
- no qualifying segregation likelihood ratio identified
Still missing
- No family-based likelihood ratio meeting BS4 thresholds was documented.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or exon-level loss-of-function variant, so PVS1 is not applicable. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 applies to qualifying loss-of-function variants
Evidence considered
- p.(Cys64Tyr) missense change
- generic PVS1 scaffold did not place this variant in a null-variant bucket
Sources
PS2 N/APS2 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks PS2 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
PM1 N/APM1 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks PM1 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
PM4 N/APM4 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks PM4 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
PM5 N/AUnder the ENIGMA BRCA1 specification, PM5 is used for protein-termination variants in exons where a different pathogenic protein-termination variant has been observed; this missense variant does not meet that variant-type requirement. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5_PTC applies to qualifying PTC variants only
Evidence considered
- missense variant p.(Cys64Tyr)
- PM5_PTC rule is restricted to PTC variants
Sources
PM6 N/APM6 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks PM6 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
PP2 N/APP2 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks PP2 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
BP2 N/ABP2 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks BP2 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
BP3 N/ABP3 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks BP3 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
BP6 N/ABP6 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 marks BP6 as not applicable
Evidence considered
- ENIGMA BRCA1 criterion applicability table
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.191G>A
- Protein (HGVS p.)
- NP_009225.1:p.(Cys64Tyr)
- GRCh38
- chr17:43106477 C>T
- GRCh37
- chr17:41258494 C>T
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
2 / 1,601,934 alleles
AF 1.25e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,601,934 alleles · 0 hom
| Remaining individuals1 / 62,042 | 1.6e-05 |
| European (non-Finnish)1 / 1,170,064 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24849e-06; MAF= 0.00012%, 2/1601934 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61181e-05; MAF= 0.00161%, 1/62042 alleles, homozygotes = 0).
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 RING domain, and the reviewed bioinformatic evidence supports a deleterious effect: BayesDel no-AF is 0.557106, which is above the ENIGMA PP3 threshold of 0.28, and SpliceAI predicts splice impact with a maximum delta score of 0.87, which is above the splice threshold of 0.2. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for damaging BayesDel and/or predicted splice impact
Evidence considered
- RING domain location
- BayesDel noAF 0.557106
- SpliceAI max delta 0.87
Sources
BP4 This missense variant is in the BRCA1 RING domain, but the predictive evidence does not support a benign effect: BayesDel no-AF is 0.557106, which is above the BP4 benign threshold of <=0.15, and SpliceAI is 0.87, which is above the <=0.1 threshold. BP4 is therefore not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 rule
Evidence considered
- BayesDel noAF 0.557106
- SpliceAI max delta 0.87
- BP4 thresholds: BayesDel <=0.15 and SpliceAI <=0.1
Sources
BP7 mRNA studies reported no aberration, but this missense variant lies within the BRCA1 RING domain and ENIGMA requires BS3 for BP7_Strong RNA in this setting; because BS3 is not supported and the functional evidence supports damage, BP7 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 RNA rule for missense variants in functional domains
Evidence considered
- RING domain location
- mRNA note: no aberration in 2 studies
- BS3 not supported
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.87).
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
2 / 1,601,934 recorded alleles
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/54400/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41258494-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43106477-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.191G…
- OncoKB ↗www.oncokb.org/gene/BRCA1/C64Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.191G%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
This variant is present in gnomAD v4.1 (AF= 1.24849e-06; MAF= 0.00012%, 2/1601934 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.61181e-05; MAF= 0.00161%, 1/62042 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.87).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.