About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.5073A>G, p.(Thr1691=)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 (non-cancer, exome subset) and is present at extremely low frequency in gnomAD v4.1 (1/1,607,416 alleles; AF=6.22e-7; no homozygotes). Under ENIGMA rules, PM2_Supporting applies when a variant is absent from gnomAD v2.1 and v3.1 non-cancer populations.
PP3Supporting
PP3 · supporting
SpliceAI predicts a splicing impact for this silent variant with a max delta score of 0.71 (donor loss: DS_DL=0.71, DP_DL=-1), exceeding the ENIGMA PP3 threshold of ≥0.2 for predicted splicing alterations. Under ENIGMA rules, PP3 at Supporting strength applies to silent variants with SpliceAI ≥0.2 irrespective of location within clinically important functional domains.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ENIGMA BRCA1/2 v1.2 point-based classification: PM2_Supporting (+1) + PP3_Supporting (+1) = +2 total pathogenic points. No benign criteria are met. The total of +2 falls within the ENIGMA VUS range (-1 to +5). No explicit ENIGMA Table 3 combination rule matches '2 Supporting only', and the generic ACMG/AMP 2015 rules also yield VUS (no PVS1, PS, or PM criteria are met to trigger a Pathogenic or Likely Pathogenic 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
1 / 1,607,416 alleles
gnomAD v4.1: 1 / 1,607,416 alleles. Recorded AF 6.22116e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.710 maximum delta
Recorded SpliceAI maximum delta score: 0.710. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.
26 criteria with recorded statuses: 2 met · 7 not met · 6 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
NM_007294.3:c.5073A>G (p.Thr1691=) is a synonymous variant in exon 16 of BRCA1, located within the BRCT domain (aa 1650-1857), a clinically important functional domain.
The variant is absent from gnomAD v2.1 and is present at extremely low frequency in gnomAD v4.1 (1/1,607,416 alleles; AF=6.22e-7), meeting PM2_Supporting under ENIGMA population frequency criteria.
SpliceAI predicts a donor loss effect with a max delta score of 0.71 (DS_DL=0.71), exceeding the ENIGMA PP3 threshold of 0.2 for predicted splicing impact in silent variants, meeting PP3 at Supporting strength.
No case-control data (PS4), cosegregation evidence (PP1), or non-segregation evidence (BS4) were identified for this variant.
BP4 is not met because SpliceAI predicts splicing impact (0.71 > 0.1 threshold). BP1 is not applicable because the variant lies within the BRCT clinically important functional domain and has predicted splicing impact. BP7_Supporting is not met because BP4 is a prerequisite.
No functional assay data from calibrated studies were identified in ENIGMA Table 9 or ST4. The Findlay et al. 2018 (PMID:30209399) saturation genome editing study covers this region, but the variant-specific functional score could not be retrieved from the inaccessible full-text supplementary data, leaving PS3 and BS3 unassessed.
No clinical-history likelihood ratio data were available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 table, leaving PP4 and BP5 unassessed.
Applying the ENIGMA point-based classification system: PM2_Supporting (+1, pathogenic) + PP3_Supporting (+1, pathogenic) = +2 total. With no benign criteria met and only two pathogenic Supporting criteria, the total points (+2) fall within the VUS range (-1 to +5).
However, the SpliceAI prediction of donor loss (delta 0.71) suggests this synonymous variant may alter splicing, and definitive classification requires functional characterization via mRNA transcript analysis and/or retrieval of the Findlay et al. 2018 saturation genome editing functional score to resolve PS3/BS3.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 (non-cancer, exome subset) and is present at extremely low frequency in gnomAD v4.1 (1/1,607,416 alleles; AF=6.22e-7; no homozygotes). Under ENIGMA rules, PM2_Supporting applies when a variant is absent from gnomAD v2.1 and v3.1 non-cancer populations. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome)
- gnomAD v4.1: 1/1
- 607
- 416 alleles
- AF=6.22e-7
- 0 homozygotes
- Highest subpopulation frequency: European (non-Finnish)
- 1/1
- 173
- 898 alleles
Sources
PP3 SupportingSpliceAI predicts a splicing impact for this silent variant with a max delta score of 0.71 (donor loss: DS_DL=0.71, DP_DL=-1), exceeding the ENIGMA PP3 threshold of ≥0.2 for predicted splicing alterations. Under ENIGMA rules, PP3 at Supporting strength applies to silent variants with SpliceAI ≥0.2 irrespective of location within clinically important functional domains. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.71 (donor loss prediction at -1 position)
- SpliceAI DS_DL=0.71
- DS_AL=0.17
- DS_DG=0.06
- DS_AG=0.0
- Silent variant with predicted splicing impact meeting PP3 threshold (≥0.2)
Sources
Not met · 7 · evaluated, threshold not reached
PS4 No case-control study demonstrating significantly increased prevalence of c.5073A>G in affected individuals versus controls (p≤0.05 and OR≥4) was identified. The variant is absent from ClinVar, and no published case-control data for this specific variant were found in the literature. Details ▾Hide ▴
PP1 No cosegregation data were identified for c.5073A>G in any published study or database. No LOD score or quantitative cosegregation analysis meeting the ENIGMA LR thresholds (≥2.08 for Supporting) was found. Details ▾Hide ▴
Evidence considered
- No cosegregation data identified in literature or databases
Still missing
- No family segregation studies available for this rare variant
Sources
BA1 ENIGMA BA1 requires a filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 or v3.1 non-cancer populations. The variant is absent from gnomAD v2.1 and has an allele frequency of 6.22e-7 (0.00006%) in gnomAD v4.1, well below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=6.22e-7 (0.00006%)
- far below BA1 threshold of 0.1%
Sources
BS1 ENIGMA BS1_Strong requires FAF > 0.01% and BS1_Supporting requires FAF > 0.002% and ≤ 0.01%. The variant has an allele frequency of 6.22e-7 (0.000062%) in gnomAD v4.1, which falls below both BS1 thresholds. The variant is absent from gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=6.22e-7
- below BS1_Supporting threshold of 0.002%
- gnomAD v2.1: absent
Sources
BS4 No data demonstrating lack of segregation of c.5073A>G in affected family members were identified. No quantitative cosegregation analysis showing an LR meeting the ENIGMA BS4 thresholds (≤0.48 for Supporting) was found in the literature or databases. Details ▾Hide ▴
Evidence considered
- No non-segregation data identified in literature or databases
Still missing
- No family non-segregation data available for this rare variant
Sources
BP4 ENIGMA BP4_Supporting for a silent variant inside a clinically important functional domain requires no predicted splicing impact (SpliceAI ≤0.1). The variant is located within the BRCT domain (aa 1650-1857), and SpliceAI predicts a splicing alteration (max delta=0.71, exceeding 0.1). BP4 is therefore not met. Details ▾Hide ▴
Evidence considered
- Residue T1691 is within the BRCT domain
- SpliceAI max delta = 0.71 exceeds BP4 threshold of ≤0.1
Sources
BP7 ENIGMA BP7_Strong (RNA) requires a well-established mRNA assay showing no splicing aberration, which is not available for this variant. BP7_Supporting for silent variants inside a clinically important functional domain requires BP4 to be met first; since BP4 is not met (SpliceAI predicts splicing impact), BP7_Supporting cannot be applied. Details ▾Hide ▴
Evidence considered
- No mRNA assay data available for BP7_Strong (RNA)
- BP4 not met
- so BP7_Supporting precondition unsatisfied
Still missing
- No mRNA transcript analysis available for this variant
Sources
Not assessed · 6 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic comparator variant with the same predicted amino acid change or splicing impact at this residue was identified in available evidence sources. This is a synonymous variant, and ENIGMA PS1 rules for missense substitutions require a same-residue pathogenic missense comparator; PS1 for splicing impact requires a reference variant with the same predicted splicing consequence, which was not found. Details ▾Hide ▴
Evidence considered
- No known pathogenic comparator at this position identified
Still missing
- No comparator variant with matching predicted splicing impact found in curated databases
Sources
PS3 The variant c.5073A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4 (full functional assay dataset). Although the saturation genome editing study by Findlay et al. (PMID:30209399) covers the BRCA1 DNA binding domain and may include functional scores for this position, the full-text could not be accessed to verify the variant-specific functional score and determine whether it meets the calibrated thresholds for PS3 strength assignment. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9 curated functional results
- Findlay et al. 2018 saturation genome editing covers this region but full-text not accessible for variant-specific score extraction
Still missing
- Functional score from Findlay et al. 2018 supplementary data not retrieved
- full-text unavailable for verification
Sources
PP4 The variant c.5073A>G was not found in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No clinical-history LR data is available to adjudicate PP4 under the ENIGMA multifactorial clinical data framework. Details ▾Hide ▴
Evidence considered
- Variant not listed in Li et al. 2020 BRCA1 clinical_history_LR table
Still missing
- No clinical-history LR data available for this variant
Sources
BS2 No data were identified regarding observation of this variant in homozygous or compound heterozygous state in individuals without Fanconi anemia phenotype. BS2 under ENIGMA requires documented absence of recessive disease features in individuals with biallelic variants, which cannot be assessed from available evidence. Details ▾Hide ▴
Evidence considered
- No homozygous or compound heterozygous observations available
- No Fanconi anemia phenotype data for variant carriers
Still missing
- No biallelic observation data available to evaluate BS2
Sources
BS3 The variant c.5073A>G is not listed in ENIGMA Table 9 (curated functional assay results assigning BS3 codes) or Supplementary Table 4 (full functional assay dataset). While Findlay et al. 2018 (PMID:30209399) saturation genome editing assay covers all single nucleotide variants in the BRCA1 DNA binding domain including this position, the full-text supplementary data could not be accessed to retrieve the variant-specific functional score and determine whether it meets the calibrated benign functional threshold for BS3 assignment. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9 curated BS3 assignments
- Findlay et al. 2018 saturation genome editing covers this region but full-text not accessible for variant-specific score
Still missing
- Functional score from Findlay et al. 2018 supplementary data not retrieved
Sources
BP5 The variant c.5073A>G was not found in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No clinical-history LR data is available to adjudicate BP5 under the ENIGMA multifactorial clinical data framework. Details ▾Hide ▴
Evidence considered
- Variant not listed in Li et al. 2020 BRCA1 clinical_history_LR table
Still missing
- No clinical-history LR data available for this variant
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.3:c.5073A>G is a synonymous variant (p.Thr1691=). It is not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus change) and no mRNA assay data demonstrating a damaging effect on transcript profile is available for this specific variant to invoke PVS1(RNA). PVS1 does not apply. Details ▾Hide ▴
Evidence considered
- Variant is synonymous (p.Thr1691=)
- not a null variant
- Not at canonical ±1
- 2 splice consensus position
- No mRNA assay data available for PVS1(RNA) pathway
Sources
PS2 VCEPENIGMA BRCA1/2 specification v1.2 marks PS2 as Not Applicable. Details ▾Hide ▴
PM1 VCEPENIGMA BRCA1/2 specification v1.2 marks PM1 as Not Applicable. Details ▾Hide ▴
PM5 N/AUnder ENIGMA BRCA1/2 specification, PM5 is repurposed for PTC (protein termination codon) variants with PVS1 applied, to capture additional weight from proven pathogenic PTCs in the same exon. This variant is synonymous (p.Thr1691=), not a PTC, and PVS1 is not applicable. Classic same-residue missense PM5 is not operative under this framework. Details ▾Hide ▴
Evidence considered
- Synonymous variant
- not a PTC
- ENIGMA PM5 is PTC-only logic
Sources
cspec ↗pm5_candidates
PM6 VCEPENIGMA BRCA1/2 specification v1.2 marks PM6 as Not Applicable. Details ▾Hide ▴
PP2 VCEPENIGMA BRCA1/2 specification v1.2 marks PP2 as Not Applicable. Details ▾Hide ▴
PP5 VCEPENIGMA BRCA1/2 specification v1.2 marks PP5 as Not Applicable. Details ▾Hide ▴
BP1 N/AENIGMA BP1_Strong requires a silent substitution outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). The variant c.5073A>G encodes p.Thr1691=, which lies within the BRCT domain (aa 1650-1857), a clinically important functional domain. Additionally, SpliceAI predicts splicing impact (max delta=0.71). Neither condition for BP1 is satisfied. Details ▾Hide ▴
Evidence considered
- Residue T1691 is within the BRCT domain (aa 1650-1857)
- a clinically important functional domain
- SpliceAI max delta = 0.71 predicts splicing impact
- exceeding cutoff of ≤0.1
Sources
BP2 VCEPENIGMA BRCA1/2 specification v1.2 marks BP2 as Not Applicable. Details ▾Hide ▴
BP6 VCEPENIGMA BRCA1/2 specification v1.2 marks BP6 as Not Applicable. Details ▾Hide ▴
PS5 N/APS5 is not listed in the ENIGMA BRCA1/2 v1.2 specification criteria. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.5073A>G
- Protein (HGVS p.)
- NP_009225.1:p.(Thr1691=)
- GRCh38
- chr17:43067609 T>C
- GRCh37
- chr17:41219626 T>C
- ClinVar
- 869070, 868528, 868355, 868056, 867520, 867517, 801084, 427336, 232795, 232356
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
1 / 1,607,416 alleles
AF 6.22e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,607,416 alleles · 0 hom
| European (non-Finnish)1 / 1,173,898 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.22116e-07; MAF= 0.00006%, 1/1607416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51863e-07; MAF= 0.00009%, 1/1173898 alleles, homozygotes = 0).
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 SupportingSpliceAI predicts a splicing impact for this silent variant with a max delta score of 0.71 (donor loss: DS_DL=0.71, DP_DL=-1), exceeding the ENIGMA PP3 threshold of ≥0.2 for predicted splicing alterations. Under ENIGMA rules, PP3 at Supporting strength applies to silent variants with SpliceAI ≥0.2 irrespective of location within clinically important functional domains. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.71 (donor loss prediction at -1 position)
- SpliceAI DS_DL=0.71
- DS_AL=0.17
- DS_DG=0.06
- DS_AG=0.0
- Silent variant with predicted splicing impact meeting PP3 threshold (≥0.2)
Sources
BP4 ENIGMA BP4_Supporting for a silent variant inside a clinically important functional domain requires no predicted splicing impact (SpliceAI ≤0.1). The variant is located within the BRCT domain (aa 1650-1857), and SpliceAI predicts a splicing alteration (max delta=0.71, exceeding 0.1). BP4 is therefore not met. Details ▾Hide ▴
Evidence considered
- Residue T1691 is within the BRCT domain
- SpliceAI max delta = 0.71 exceeds BP4 threshold of ≤0.1
Sources
BP7 ENIGMA BP7_Strong (RNA) requires a well-established mRNA assay showing no splicing aberration, which is not available for this variant. BP7_Supporting for silent variants inside a clinically important functional domain requires BP4 to be met first; since BP4 is not met (SpliceAI predicts splicing impact), BP7_Supporting cannot be applied. Details ▾Hide ▴
Evidence considered
- No mRNA assay data available for BP7_Strong (RNA)
- BP4 not met
- so BP7_Supporting precondition unsatisfied
Still missing
- No mRNA transcript analysis available for this variant
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.71).
2 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 30209399 ↗Accurate classification of BRCA1 variants with saturation genome editing.Findlay GM et al. · 2018No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,607,416 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.710
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_007294.3%3Ac.5073A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41219626-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43067609-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.5073…
- OncoKB ↗www.oncokb.org/gene/BRCA1/T1691=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.5073A%3EG
- 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= 6.22116e-07; MAF= 0.00006%, 1/1607416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51863e-07; MAF= 0.00009%, 1/1173898 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.71).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.