About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.83T>C, p.(Leu28Pro)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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 (exome) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting requirement: absent from controls in an outbred population in both gnomAD non-cancer subsets.
PP3Supporting
PP3 · supporting
The variant is a missense substitution (p.Leu28Pro) located within the BRCA1 RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.451556, which exceeds the ENIGMA PP3 threshold of ≥0.28 for predicted deleterious protein impact. SpliceAI max delta is 0.00, consistent with a protein-change mechanism rather than splicing. REVEL score of 0.832 provides additional in silico support.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Not classified
No source classification-combination explanation was recorded.
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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
6 Uncertain significance · 1 Likely pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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.
27 criteria with recorded statuses: 2 met · 5 not met · 7 not assessed · 13 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.83T>C (p.Leu28Pro) is a missense variant in BRCA1 exon 3, located within the RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications.
This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.
In silico analysis predicts a deleterious effect: BayesDel no-AF score of 0.451556 exceeds the ENIGMA PP3 threshold of 0.28 for predicted damaging protein impact, and REVEL score is 0.832. SpliceAI predicts no splicing impact (max delta 0.00). These findings meet ENIGMA PP3 at Supporting strength.
BP4 is not met because the BayesDel score (0.451556) exceeds the ENIGMA benign prediction threshold of 0.15.
The variant is classified as Uncertain Significance (VUS) in ClinVar by the ENIGMA expert panel (ClinVar ID 55732), with 6 clinical laboratories reporting VUS and 1 reporting Likely Pathogenic.
Functional evidence (PS3/BS3) could not be assessed: ENIGMA Table 9 does not list c.83T>C, OncoKB classifies the effect as Inconclusive, and no publication abstract confirmed variant-specific functional data. The variant lies within the RING domain targeted by saturation genome editing studies (Findlay 2018, Starita 2015) but full-text verification is needed.
Clinical evidence (PP4/BP5 via Li et al. 2020 clinical history LR; PP1/BS4 via cosegregation) could not be assessed due to unavailability of variant-level data in the extracted materials.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting requirement: absent from controls in an outbred population in both gnomAD non-cancer subsets. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 exome non-cancer
- absent from gnomAD v4.1 non-cancer.
Sources
PP3 SupportingThe variant is a missense substitution (p.Leu28Pro) located within the BRCA1 RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.451556, which exceeds the ENIGMA PP3 threshold of ≥0.28 for predicted deleterious protein impact. SpliceAI max delta is 0.00, consistent with a protein-change mechanism rather than splicing. REVEL score of 0.832 provides additional in silico support. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = 0.451556 (≥0.28 threshold)
- REVEL = 0.832
- SpliceAI max delta = 0.00
- located within RING domain (aa 2-101).
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No previously classified pathogenic missense variant has been identified at BRCA1 codon 28. The ClinVar record for this variant (ID 55732) is classified as Uncertain Significance by the ENIGMA expert panel, and no publication abstract confirms the existence of a known pathogenic L28 substitution. PS1 requires a same-residue pathogenic comparator, which is absent. Details ▾Hide ▴
PS4 No case-control study demonstrating significantly increased prevalence in affected individuals (p≤0.05, OR≥4) has been identified for this variant. ENIGMA PS4 requires formal case-control comparison; available ClinVar and gnomAD data do not provide this. Details ▾Hide ▴
Evidence considered
- No case-control study with significant OR identified.
Still missing
- No case-control data available for PS4 assessment.
Sources
cspec ↗15235020
BA1 The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires a filter allele frequency >0.001 (0.1%) in gnomAD non-cancer, non-founder populations. Absence does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- FAF effectively 0
- far below BA1 threshold of >0.001.
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BS1_Supporting requires FAF >0.00002 and BS1_Strong requires FAF >0.0001. Absence does not meet either threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- FAF effectively 0
- below BS1 thresholds.
Sources
BP4 ENIGMA BP4 for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1. The BayesDel no-AF score for this variant is 0.451556, which exceeds the 0.15 threshold for benign prediction. Therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = 0.451556 (>0.15 BP4 threshold)
- SpliceAI = 0.00
- inside RING domain.
Sources
Not assessed · 7 · no assessment recorded
PS3 ENIGMA Table 9 (curated functional assay results) does not list c.83T>C. The functional assay supplementary dataset (ST4) excerpt did not include this variant. Key functional studies of the BRCA1 RING domain (Findlay 2018 PMID:30209399, Starita 2015 PMID:25823446, Clark 2022 PMID:35659930) do not mention c.83T>C or p.Leu28Pro in their abstracts. OncoKB classifies the functional effect as 'Inconclusive.' Full-text files are not available for verification. Without variant-specific functional evidence, PS3 cannot be assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 does not list c.83T>C
- OncoKB = Inconclusive
- no variant-specific functional data confirmed in available abstracts.
Still missing
- Functional assay result for p.Leu28Pro not confirmed in any available source.
- Full-text of Findlay 2018
- Starita 2015
- and Clark 2022 needed to verify variant-specific functional data.
Sources
PP1 No cosegregation data identified for this variant. No published family studies with quantitative cosegregation analysis found. ENIGMA PP1 requires co-segregation with disease in multiple affected family members with LR ≥2.08. Details ▾Hide ▴
Evidence considered
- No cosegregation or family study data available.
Still missing
- Cosegregation data not available.
Sources
PP4 ENIGMA PP4 requires multifactorial likelihood clinical data with LR ≥2.08 (Supporting). The Li et al. 2020 clinical history LR table (PMID:31853058) may contain data for c.83T>C, but the variant-level LR could not be verified from the extracted VCEP materials. No clinical history LR data is confirmed for this variant. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 clinical history LR table (PMID:31853058) may contain variant-level data
- not verified in available extracts.
Still missing
- Clinical history LR from PMID:31853058 not verified for c.83T>C.
- Multifactorial likelihood data from Parsons et al. 2019 (PMID:31131967) not verified.
Sources
BS2 ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia features. No such data is available for this variant. Details ▾Hide ▴
Evidence considered
- No data on observation in healthy adults without FA phenotype.
Still missing
- No BS2-relevant observational data available.
Sources
BS3 ENIGMA Table 9 does not list a pre-assigned BS3 code for c.83T>C. OncoKB classifies the biological effect as 'Inconclusive.' No variant-specific functional evidence demonstrating no damaging effect on protein function was confirmed in available publication abstracts. Full-text verification of functional assay data (Findlay 2018, Starita 2015, Clark 2022) is needed. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 does not list c.83T>C
- OncoKB = Inconclusive
- no benign functional data confirmed.
Still missing
- No variant-specific benign functional assay result confirmed.
- ENIGMA ST4 full dataset and full-text of key functional papers not verified for c.83T>C.
Sources
BS4 No segregation data demonstrating lack of cosegregation in affected family members has been identified for this variant. ENIGMA BS4 requires quantitative cosegregation analysis with LR ≤0.48 (Supporting). Details ▾Hide ▴
Evidence considered
- No segregation or family study data available.
Still missing
- No cosegregation data for BS4 assessment.
Sources
BP5 ENIGMA BP5 requires multifactorial likelihood clinical data supporting benignity (LR ≤0.48 for Supporting). The Li et al. 2020 clinical history LR table (PMID:31853058) may contain data for c.83T>C, but the variant-level LR could not be verified. No clinical history LR data is confirmed for this variant. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 clinical history LR table (PMID:31853058) may contain variant-level data
- not verified in available extracts.
Still missing
- Clinical history LR from PMID:31853058 not verified for c.83T>C.
- Multifactorial likelihood data from Parsons et al. 2019 (PMID:31131967) not verified.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, exon deletion) under ENIGMA BRCA1/2 v1.2.0. NM_007294.3:c.83T>C is a missense variant (p.Leu28Pro) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 28
- ENIGMA PVS1 restricted to null variants only.
Sources
cspec ↗pvs1_variant_assessment
PS2 VCEPPS2 (de novo) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. The criterion is superseded by ENIGMA's gene-specific bioinformatic code (PP3/BP4) and domain-aware PS1 rules. Details ▾Hide ▴
PM5 N/AUnder ENIGMA BRCA1/2 v1.2.0, PM5 is repurposed for PTC (protein termination codon) logic applicable to truncating variants in exons with established pathogenic PTCs. This is a missense variant; the PM5_PTC framework does not apply. Classic same-residue missense PM5 is also not applicable per the ENIGMA specification. Details ▾Hide ▴
Evidence considered
- Missense variant
- ENIGMA PM5 restricted to PTC logic
- pm5_candidates.json confirms not applicable.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 (de novo) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
PP5 VCEPPP5 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
BP1 N/AENIGMA BP1 applies to missense variants located OUTSIDE a clinically important functional domain with no splicing predicted (SpliceAI ≤0.1). This variant is at position 28, which is INSIDE the RING domain (aa 2-101), a clinically important functional domain. BP1 therefore does not apply. Details ▾Hide ▴
Evidence considered
- Position 28 is within RING domain (aa 2-101)
- SpliceAI = 0.00
- BP1 requires location outside functional domain.
Sources
BP2 VCEPBP2 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0 (in-frame indels only; not relevant for substitution variants). Details ▾Hide ▴
BP6 VCEPBP6 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
BP7 N/AENIGMA BP7_Supporting applies to silent variants inside functional domains (if BP4 met) or intronic variants outside conserved splice motifs (if BP4 met). This is a missense variant and does not qualify for either BP7_Supporting path. ENIGMA BP7_Strong(RNA) applies to missense variants outside functional domains with mRNA assay evidence; this variant is inside the RING domain and lacks confirmed mRNA assay data. BP7 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7_Supporting paths require silent or intronic variant
- BP7_Strong(RNA) requires location outside functional domain or BS3 prerequisite.
Sources
PS5 N/APP5 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.83T>C
- Protein (HGVS p.)
- NP_009225.1:p.(Leu28Pro)
- GRCh38
- chr17:43115777 A>G
- GRCh37
- chr17:41267794 A>G
- ClinVar
- 55732
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
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.832
- BayesDel
- 0.452
How the predictions were used
PP3 SupportingThe variant is a missense substitution (p.Leu28Pro) located within the BRCA1 RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.451556, which exceeds the ENIGMA PP3 threshold of ≥0.28 for predicted deleterious protein impact. SpliceAI max delta is 0.00, consistent with a protein-change mechanism rather than splicing. REVEL score of 0.832 provides additional in silico support. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = 0.451556 (≥0.28 threshold)
- REVEL = 0.832
- SpliceAI max delta = 0.00
- located within RING domain (aa 2-101).
Sources
BP4 ENIGMA BP4 for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1. The BayesDel no-AF score for this variant is 0.451556, which exceeds the 0.15 threshold for benign prediction. Therefore BP4 is not met. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF = 0.451556 (>0.15 BP4 threshold)
- SpliceAI = 0.00
- inside RING domain.
Sources
BP7 N/AENIGMA BP7_Supporting applies to silent variants inside functional domains (if BP4 met) or intronic variants outside conserved splice motifs (if BP4 met). This is a missense variant and does not qualify for either BP7_Supporting path. ENIGMA BP7_Strong(RNA) applies to missense variants outside functional domains with mRNA assay evidence; this variant is inside the RING domain and lacks confirmed mRNA assay data. BP7 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7_Supporting paths require silent or intronic variant
- BP7_Strong(RNA) requires location outside functional domain or BS3 prerequisite.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.832. BayesDel score = 0.451556.
8 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 16403807 ↗Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility.Morris JR et al. · 2006No paper-specific finding is recorded.
-
PMID 22034435 ↗BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity.No paper-specific finding is recorded.
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PMID 15235020 ↗Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.Abkevich V et al. · 2004No paper-specific finding is recorded.
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PMID 21520333 ↗LOVD v.2.0: the next generation in gene variant databases.Fokkema IF et al. · 2011No paper-specific finding is recorded.
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 25823446 ↗Massively Parallel Functional Analysis of BRCA1 RING Domain Variants.Starita LM et al. · 2015No paper-specific finding is recorded.
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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 0.000
Open source ↗
ClinVar
6 Uncertain significance · 1 Likely pathogenic
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/55732/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41267794-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43115777-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.83T%…
- OncoKB ↗www.oncokb.org/gene/BRCA1/L28P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.83T%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 Uncertain significance (6 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 55732)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.832. BayesDel score = 0.451556.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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.