About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.131G>A, p.(Cys44Tyr)
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
ENIGMA BRCA1 Table 9 assigns PS3_Strong to c.131G>A (p.Cys44Tyr), reporting two calibrated studies showing protein function similar to pathogenic control variants. Supplementary functional data also show complete functional impact/loss of function.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and gnomAD v4.1 in the reviewed population datasets, supporting rarity consistent with PM2_Supporting under the BRCA1 ENIGMA framework.
PP3Supporting
PP3 · supporting
This missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain in the ENIGMA BRCA1 framework, and the reviewed bioinformatic dataset shows a BayesDel score of 0.57077, above the PP3 threshold. SpliceAI predicts no meaningful splice impact, supporting a protein-based deleterious interpretation.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Official ENIGMA BRCA1/BRCA2 VCEP final-classification framework (Specifications v1.2 Table 4 combination rules) applied to the adjudicated criteria.
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 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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as 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
Cancer Hotspots ↗
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 · 6 not met · 8 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.131G>A (p.Cys44Tyr) variant has been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including ENIGMA expert panel review.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
Calibrated functional studies have shown a damaging loss-of-function effect for p.Cys44Tyr, and ENIGMA BRCA1 Table 9 assigns PS3_Strong based on these data.
The missense change affects the BRCA1 RING domain, a clinically important functional domain, with BayesDel 0.57077 supporting deleterious impact, while SpliceAI predicts no meaningful splice effect (max delta 0.01).
No criteria match.
Met · 3
PS3 StrongENIGMA BRCA1 Table 9 assigns PS3_Strong to c.131G>A (p.Cys44Tyr), reporting two calibrated studies showing protein function similar to pathogenic control variants. Supplementary functional data also show complete functional impact/loss of function. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS3 uses calibrated functional studies; Table 9 provides code recommendations.
Evidence considered
- Table 9 row: BRCA1 c.131G>A p.(Cys44Tyr) -> PS3 Strong.
- Table 9 cites Findlay 2018 (PMID:30209399) and Bouwman 2020 (PMID:32546644).
- Supplementary Table 4 lists c.131G>A as Functional impact - complete / LOF.
Sources
cspec ↗Specifications_Table9_V1.2_2024-11-18.xlsxSupplementaryTables_V1.2_2024-11-18.xlsx3020939932546644
PM2 SupportingThe variant is absent from gnomAD v2.1 and gnomAD v4.1 in the reviewed population datasets, supporting rarity consistent with PM2_Supporting under the BRCA1 ENIGMA framework. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2 is applied at Supporting strength for absence from controls in qualifying gnomAD datasets.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- ENIGMA BRCA1 uses PM2 at Supporting strength for absence from controls.
Still missing
- The reviewed workspace includes gnomAD v2.1 and v4.1 rather than a direct v3.1 record; confirmatory population review can be considered if strict version matching is required.
Sources
PP3 SupportingThis missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain in the ENIGMA BRCA1 framework, and the reviewed bioinformatic dataset shows a BayesDel score of 0.57077, above the PP3 threshold. SpliceAI predicts no meaningful splice impact, supporting a protein-based deleterious interpretation. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for missense variants in clinically important domains with BayesDel no-AF ≥0.28.
Evidence considered
- ENIGMA BRCA1 PP3 applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.28.
- Supplementary Table ST13 lists BRCA1 c.131G>A p.Cys44Tyr in the RING domain with BayesDel 0.57077.
- SpliceAI max delta score is 0.01.
Sources
Not met · 6 · evaluated, threshold not reached
BA1 The variant is absent from the reviewed gnomAD datasets and does not meet the high population frequency threshold required for BA1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires FAF above the stand-alone benign threshold.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- ENIGMA BRCA1 BA1 requires FAF >0.1%.
Sources
BS1 The variant is absent from the reviewed gnomAD datasets and does not meet the population frequency threshold required for BS1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 requires elevated FAF in qualifying populations.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- ENIGMA BRCA1 BS1 requires FAF above benign strong/supporting thresholds.
Sources
BS3 Curated ENIGMA functional evidence supports a damaging effect rather than a neutral effect; Table 9 assigns PS3_Strong, so BS3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS3 requires well-established studies showing no damaging effect.
Evidence considered
- Table 9 assigns PS3 Strong to c.131G>A.
- Supplementary Table 4 lists complete functional impact / loss of function.
Sources
Specifications_Table9_V1.2_2024-11-18.xlsxSupplementaryTables_V1.2_2024-11-18.xlsx3020939932546644
BP1 BP1_Strong is restricted to silent, missense, or in-frame variants outside a clinically important functional domain with no splicing effect. This variant is within the BRCA1 RING domain and has damaging functional evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong applies only outside clinically important functional domains with no predicted splice effect.
Evidence considered
- BRCA1 aa 44 lies within the RING domain (aa 2-101) defined by ENIGMA as clinically important.
- SpliceAI max delta score is 0.01.
- Functional evidence supports loss of function rather than benignity.
Sources
BP4 Although SpliceAI predicts no significant splice impact, BP4 for missense variants inside a clinically important functional domain also requires BayesDel no-AF ≤0.15. The reviewed bioinformatic dataset shows BayesDel 0.57077, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants in a clinically important domain requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- ST13 BayesDel score: 0.57077.
- SpliceAI max delta score: 0.01.
- ENIGMA BRCA1 BP4 inside a clinically important domain requires BayesDel ≤0.15 and SpliceAI ≤0.1.
Sources
BP7 BP7 in the ENIGMA BRCA1 framework is intended for silent or intronic variants, or for RNA-only evidence showing no damaging effect. This is a missense variant within a clinically important domain, and benign RNA-only or neutral functional evidence was not identified. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 is primarily for silent/intronic variants or RNA-only benign evidence, with additional restrictions for missense variants in clinically important domains.
Evidence considered
- Variant type is missense, not silent or intronic.
- SpliceAI predicts no major splice effect, but BP7 for missense variants in a clinically important domain would require appropriate benign functional context not present here.
- Table 9 supports PS3 rather than BS3/BP7.
Still missing
- No qualifying benign RNA assay result was identified.
Sources
Not assessed · 8 · no assessment recorded
PS1 No reviewed source established a separately classified pathogenic missense variant causing the same amino acid substitution or an equivalent proven splicing effect for PS1 application. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS1 requires same amino acid change or same splice effect as a previously classified pathogenic/likely pathogenic variant.
Evidence considered
- ENIGMA BRCA1 PS1 requires a previously classified pathogenic or likely pathogenic variant with the same amino acid change or same predicted splice effect.
- ClinVar confirms classification of this specific variant but does not by itself establish PS1.
Still missing
- A dedicated search for an alternate nucleotide change producing p.Cys44Tyr was not available in the reviewed materials.
Sources
PS4 The reviewed materials show database observations, including ClinVar submissions and one COSMIC somatic observation, but no qualifying case-control analysis with a significant enrichment over controls as required for PS4. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires significant enrichment in affected individuals versus controls.
Evidence considered
- ClinVar reports pathogenic submissions including ENIGMA expert panel review.
- COSMIC reports one somatic observation (COSV107367559, n=1).
- ENIGMA BRCA1 PS4 requires case-control evidence with p≤0.05 and OR≥4.
Still missing
- No odds ratio, confidence interval, or qualifying case-control dataset was identified.
Sources
PM3 No evidence was identified for biallelic BRCA1 findings in a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 cannot be applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 requires Fanconi anemia-related proband evidence and point-based scoring.
Evidence considered
- ENIGMA BRCA1 PM3 is reserved for BRCA1/2-related Fanconi anemia with co-occurring variants in the same gene.
- No such case-level evidence was identified in the reviewed sources.
Still missing
- No proband-level phase data or Fanconi anemia phenotype data were available.
Sources
PP1 No quantitative segregation data were identified to support PP1. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP1 uses quantitative segregation likelihood ratios.
Evidence considered
- ENIGMA BRCA1 PP1 requires quantitative segregation evidence.
- No segregation dataset for this variant was identified in the reviewed materials.
Still missing
- No family segregation likelihood ratio or pedigree-based segregation analysis was available.
Sources
cspec ↗literature_pass
PP4 No multifactorial clinical likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 uses multifactorial clinical likelihood ratios only.
Evidence considered
- ENIGMA BRCA1 PP4 is reserved for multifactorial likelihood data.
- No matching variant entry was identified in the reviewed Parsons supplementary workbook.
Still missing
- No variant-specific combined LR from multifactorial clinical data was found in the reviewed materials.
Sources
BS2 No qualifying observations in individuals without features of recessive BRCA1-related disease were identified to score BS2. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 uses a point-based framework tied to absence of recessive disease features.
Evidence considered
- ENIGMA BRCA1 BS2 requires point-based observations without Fanconi anemia features.
- No such dataset was identified in the reviewed sources.
Still missing
- No point-based BS2 evidence from adult observations or recessive disease exclusion was available.
Sources
BS4 No quantitative lack-of-segregation evidence was identified to support BS4. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS4 uses quantitative segregation likelihood ratios against pathogenicity.
Evidence considered
- ENIGMA BRCA1 BS4 requires quantitative lack-of-segregation data.
- No qualifying segregation analysis for this variant was identified.
Still missing
- No family-based segregation likelihood ratio against pathogenicity was available.
Sources
cspec ↗literature_pass
BP5 No multifactorial clinical likelihood ratio against pathogenicity was identified to support BP5 at any strength. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP5 uses multifactorial likelihood ratios against pathogenicity only.
Evidence considered
- ENIGMA BRCA1 BP5 is reserved for multifactorial likelihood data against pathogenicity.
- No matching variant entry was identified in the reviewed Parsons supplementary workbook.
Still missing
- No qualifying combined LR against pathogenicity was found.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.131G>A is a missense variant, and the reviewed evidence does not show a null effect or an RNA assay result that would justify PVS1 under the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 is for null variants or qualifying RNA-only evidence.
Evidence considered
- BRCA1 ENIGMA VCEP PVS1 applies to null variants or qualifying RNA-only functional evidence.
- SpliceAI max delta score is 0.01, with no evidence of a splice-disrupting effect.
Sources
PS2 N/APS2 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PS2 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
PM1 N/APM1 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PM1 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
PM4 N/APM4 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PM4 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
PM5 N/AUnder the ENIGMA BRCA1 specification, PM5 is defined for protein-truncating variants in eligible exons and does not apply to this missense variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 in the reviewed framework is for PTC variants with exon-specific eligibility.
Evidence considered
- ENIGMA BRCA1 PM5 rule in the reviewed specification is the PTC-based PM5_PTC framework.
- c.131G>A is a missense variant in exon 2, not a protein-truncating variant.
Sources
cspec ↗Specifications_Table4_V1.2_2024-11-18.xlsx
PM6 N/APM6 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PM6 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
PP2 N/APP2 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PP2 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
PP5 N/APP5 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists PP5 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
BP2 N/ABP2 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists BP2 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
BP3 N/ABP3 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists BP3 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
BP6 N/ABP6 is listed as not applicable in the ENIGMA BRCA1 specification. Details ▾Hide ▴
Rule
Not applicable per ENIGMA BRCA1 specification.
Evidence considered
- Case summary lists BP6 applicability as Not Applicable in the BRCA1 ENIGMA specification.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.131G>A
- Protein (HGVS p.)
- NP_009225.1:p.(Cys44Tyr)
- GRCh38
- chr17:43115729 C>T
- GRCh37
- chr17:41267746 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
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 lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain in the ENIGMA BRCA1 framework, and the reviewed bioinformatic dataset shows a BayesDel score of 0.57077, above the PP3 threshold. SpliceAI predicts no meaningful splice impact, supporting a protein-based deleterious interpretation. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 for missense variants in clinically important domains with BayesDel no-AF ≥0.28.
Evidence considered
- ENIGMA BRCA1 PP3 applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.28.
- Supplementary Table ST13 lists BRCA1 c.131G>A p.Cys44Tyr in the RING domain with BayesDel 0.57077.
- SpliceAI max delta score is 0.01.
Sources
BP4 Although SpliceAI predicts no significant splice impact, BP4 for missense variants inside a clinically important functional domain also requires BayesDel no-AF ≤0.15. The reviewed bioinformatic dataset shows BayesDel 0.57077, so BP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants in a clinically important domain requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- ST13 BayesDel score: 0.57077.
- SpliceAI max delta score: 0.01.
- ENIGMA BRCA1 BP4 inside a clinically important domain requires BayesDel ≤0.15 and SpliceAI ≤0.1.
Sources
BP7 BP7 in the ENIGMA BRCA1 framework is intended for silent or intronic variants, or for RNA-only evidence showing no damaging effect. This is a missense variant within a clinically important domain, and benign RNA-only or neutral functional evidence was not identified. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 is primarily for silent/intronic variants or RNA-only benign evidence, with additional restrictions for missense variants in clinically important domains.
Evidence considered
- Variant type is missense, not silent or intronic.
- SpliceAI predicts no major splice effect, but BP7 for missense variants in a clinically important domain would require appropriate benign functional context not present here.
- Table 9 supports PS3 rather than BS3/BP7.
Still missing
- No qualifying benign RNA assay result was identified.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
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/54199/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41267746-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43115729-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.131G…
- OncoKB ↗www.oncokb.org/gene/BRCA1/C44Y
- 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 Pathogenic (9 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB classifies this variant as Oncogenic; biological effect: Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV107367559, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.