About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.4159T>C, p.(Ser1387Pro)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BP1Strong
BP1 · strong
p.(Ser1387Pro) is a missense variant outside the ENIGMA BRCA1 clinically important domains, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the BP1_Strong threshold of 0.1. This meets ENIGMA BRCA1 BP1_Strong.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely benign.
Recorded classification: Likely benign
Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework using Table 3 adapted ACMG/AMP combination rules.
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 / 1,612,348 alleles
gnomAD v4.1: 2 / 1,612,348 alleles. Recorded AF 1.24043e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02755e-06; MAF= 0.00040%, 1/248290 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89696e-06; MAF= 0.00089%, 1/112398 alleles, homozygotes = 0).
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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
No listed criterion applied
OncoKB ↗
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: 2 met · 6 not met · 9 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.4159T>C (p.Ser1387Pro) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as Likely Benign despite conflicting individual submissions.
This variant is present at very low frequency in population databases, including gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%; grpmax FAF 2.8e-07), which is too low for BA1 or BS1 and means PM2 is not met because the variant is not absent from controls.
No exact curated functional assay result for p.(Ser1387Pro) was identified in the ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied from the available functional evidence.
In silico data support a benign interpretation under the ENIGMA BRCA1 framework because p.(Ser1387Pro) lies outside the BRCA1 clinically important domains, SpliceAI predicts no splice impact (max delta 0.00), and the missense change therefore meets BP1_Strong; BayesDel is 0.148379 and PP3 is not met.
No criteria match.
Met · 2
BP1 Strongp.(Ser1387Pro) is a missense variant outside the ENIGMA BRCA1 clinically important domains, and SpliceAI predicts no splice impact with a max delta score of 0.00, which is below the BP1_Strong threshold of 0.1. This meets ENIGMA BRCA1 BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong applies to missense variants outside clinically important domains with SpliceAI <=0.1.
Evidence considered
- Residue 1387 is outside RING aa 2-101
- coiled-coil aa 1391-1424
- and BRCT aa 1650-1857
- SpliceAI max delta 0.00
Sources
Not met · 6 · evaluated, threshold not reached
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and in gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%), so ENIGMA BRCA1 PM2_Supporting is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2 applies only when the variant is absent from gnomAD controls.
Evidence considered
- gnomAD v2.1 total AF 4.02755e-06
- gnomAD v4.1 total AF 1.24043e-06
Sources
PP3 ENIGMA BRCA1 PP3 for missense variants requires location in a clinically important functional domain with BayesDel no-AF score at least 0.28, or predicted splice impact with SpliceAI at least 0.2. p.(Ser1387Pro) lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains; BayesDel is 0.148379, SpliceAI max delta is 0.00, and REVEL is 0.481, so PP3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 missense use requires domain location plus BayesDel >=0.28, or SpliceAI >=0.2 for splicing impact.
Evidence considered
- Residue 1387 is outside ENIGMA BRCA1 clinically important domains
- BayesDel no-AF score 0.148379
- SpliceAI max delta 0.00
- REVEL score 0.481
Sources
PP4 The BRCA1 clinical-history likelihood ratio for this variant is 0.645 in 1 proband, which is below the ENIGMA PP4 threshold of 2.08 and falls in the neutral zone, so PP4 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 requires clinical-history LR >=2.08.
Evidence considered
- Clinical-history LR 0.6446937417616305
- N_Probands 1
Sources
BA1 The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is far below the ENIGMA BRCA1 BA1 threshold of 0.001, so BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires FAF >0.001 in a non-founder population.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.8e-07
Sources
BS1 The highest observed gnomAD v4.1 filter allele frequency is 2.8e-07, which is below the ENIGMA BRCA1 BS1 thresholds of greater than 0.00002 for BS1_Supporting and greater than 0.0001 for BS1, so BS1 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 requires FAF >0.00002 for supporting or >0.0001 for strong benign evidence.
Evidence considered
- gnomAD v4.1 grpmax FAF 2.8e-07
Sources
BP5 The BRCA1 clinical-history likelihood ratio for this variant is 0.645 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 BP5 requires clinical-history LR <=0.48.
Evidence considered
- Clinical-history LR 0.6446937417616305
- N_Probands 1
Sources
Not assessed · 9 · no assessment recorded
PS1 No evidence was identified showing that this variant produces the same protein change as a previously established pathogenic or likely pathogenic BRCA1 variant, and no matched splice mechanism was identified. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS1 requires the same protein or splice consequence as a previously classified pathogenic or likely pathogenic variant.
Evidence considered
- ClinVar record was reviewed
- No PS1 match was established from the available evidence
Still missing
- No validated pathogenic reference variant with the same amino-acid change was identified.
- No same-splice-effect pathogenic comparator was identified.
Sources
PS3 No calibrated variant-specific functional study supporting a damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so PS3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS3 requires well-established functional evidence showing a damaging effect.
Evidence considered
- No exact match for c.4159T>C or p.(Ser1387Pro) was found in the curated BRCA1 functional tables
Still missing
- No exact p.(Ser1387Pro) entry was identified in ENIGMA Table 9.
- No exact p.(Ser1387Pro) entry was identified in the supplementary functional assay dataset.
Sources
PS4 Available evidence does not show a case-control enrichment study or other quantitative affected-versus-control analysis meeting ENIGMA BRCA1 PS4 requirements for this variant. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires a significant increase in prevalence in affected individuals compared with controls.
Evidence considered
- ClinVar submissions were reviewed
- No PS4-level prevalence evidence was identified
Still missing
- No qualifying odds ratio or case-control dataset was identified.
Sources
PM3 No evidence was identified showing this variant in the biallelic Fanconi anemia context required for ENIGMA BRCA1 PM3 scoring. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 is scored only in the Fanconi anemia setting.
Evidence considered
- No PM3-specific proband evidence was identified
Still missing
- No qualifying recessive disease observations were identified.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in the unaffected or non-Fanconi-anemia context required for ENIGMA BRCA1 BS2 point assignment. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 is point based and depends on qualifying non-recessive-disease observations.
Evidence considered
- No BS2-specific observations were identified
Still missing
- No BS2 point-based proband data were identified.
Sources
BS3 No calibrated variant-specific functional study showing no damaging effect was identified for p.(Ser1387Pro) in the ENIGMA BRCA1 curated functional assay tables, so BS3 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS3 requires well-established functional evidence showing no damaging effect.
Evidence considered
- No exact curated BS3 assay result was identified for this variant
Still missing
- No exact p.(Ser1387Pro) entry was identified in ENIGMA Table 9.
- No exact p.(Ser1387Pro) entry was identified in the supplementary functional assay dataset.
Sources
BS4 No quantitative lack-of-segregation data were identified for this variant, so BS4 was not applied. Details ▾Hide ▴
BP7 No RNA study showing a normal transcript profile was identified for this variant, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 requires qualifying RNA evidence or specific silent/intronic contexts.
Evidence considered
- SpliceAI predicts no splice impact
- No variant-specific RNA assay was identified
Still missing
- No qualifying mRNA or splicing assay result was identified for this exact variant.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Ser1387Pro), and does not fall into the BRCA1 null-variant or canonical splice categories used for PVS1. Available splice prediction does not indicate an RNA effect that would support RNA-based PVS1 application. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 is reserved for null variants or qualifying RNA evidence.
Evidence considered
- p.(Ser1387Pro) is a missense change
- Generic PVS1 scaffold states this variant is not in a default null-variant bucket
- SpliceAI max delta score is 0.00
Sources
PS2 N/AThis framework does not use PS2 for BRCA1 variant classification. Details ▾Hide ▴
PM1 N/AThe ENIGMA BRCA1 framework does not use PM1 for BRCA1 variant classification. Details ▾Hide ▴
PM4 N/AThis framework does not use PM4 for BRCA1 variant classification. Details ▾Hide ▴
PM5 N/AIn the ENIGMA BRCA1 framework, PM5 is used as PM5_PTC for protein-truncating variants. This variant is a missense substitution and is not eligible for PM5_PTC. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 applies to qualifying PTC variants by exon.
Evidence considered
- Variant is missense
- not protein truncating
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/AThis framework does not use PM6 for BRCA1 variant classification. Details ▾Hide ▴
PP2 N/AThis framework does not use PP2 for BRCA1 variant classification. Details ▾Hide ▴
PP5 N/AThis framework does not use PP5 for BRCA1 variant classification. Details ▾Hide ▴
BP2 N/AThis framework does not use BP2 for BRCA1 variant classification. Details ▾Hide ▴
BP3 N/AThis framework does not use BP3 for BRCA1 variant classification. Details ▾Hide ▴
BP4 N/AAlthough BayesDel is 0.148379 and SpliceAI max delta is 0.00, ENIGMA BRCA1 restricts missense BP4 to variants inside clinically important functional domains. p.(Ser1387Pro) lies outside those domains, so BP4 is not applicable and benign computational evidence is captured by BP1_Strong instead. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 missense use is limited to clinically important domains with BayesDel <=0.15 and SpliceAI <=0.1.
Evidence considered
- BayesDel no-AF score 0.148379
- SpliceAI max delta 0.00
- Residue 1387 is outside ENIGMA BRCA1 clinically important domains
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.4159T>C
- Protein (HGVS p.)
- NP_009225.1:p.(Ser1387Pro)
- GRCh38
- chr17:43090970 A>G
- GRCh37
- chr17:41242987 A>G
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
2 / 1,612,348 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
1 / 248,290 alleles
AF 4.03e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,612,348 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,179,284 | 1.7e-06 |
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 v2.1
AF 4e-06 · 1 / 248,290 alleles · 0 hom
| European (non-Finnish)1 / 112,398 | 8.9e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.24043e-06; MAF= 0.00012%, 2/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69594e-06; MAF= 0.00017%, 2/1179284 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02755e-06; MAF= 0.00040%, 1/248290 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89696e-06; MAF= 0.00089%, 1/112398 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 ENIGMA BRCA1 PP3 for missense variants requires location in a clinically important functional domain with BayesDel no-AF score at least 0.28, or predicted splice impact with SpliceAI at least 0.2. p.(Ser1387Pro) lies outside the BRCA1 RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains; BayesDel is 0.148379, SpliceAI max delta is 0.00, and REVEL is 0.481, so PP3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 missense use requires domain location plus BayesDel >=0.28, or SpliceAI >=0.2 for splicing impact.
Evidence considered
- Residue 1387 is outside ENIGMA BRCA1 clinically important domains
- BayesDel no-AF score 0.148379
- SpliceAI max delta 0.00
- REVEL score 0.481
Sources
BP7 No RNA study showing a normal transcript profile was identified for this variant, so BP7 was not applied. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 requires qualifying RNA evidence or specific silent/intronic contexts.
Evidence considered
- SpliceAI predicts no splice impact
- No variant-specific RNA assay was identified
Still missing
- No qualifying mRNA or splicing assay result was identified for this exact variant.
Sources
BP4 N/AAlthough BayesDel is 0.148379 and SpliceAI max delta is 0.00, ENIGMA BRCA1 restricts missense BP4 to variants inside clinically important functional domains. p.(Ser1387Pro) lies outside those domains, so BP4 is not applicable and benign computational evidence is captured by BP1_Strong instead. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 missense use is limited to clinically important domains with BayesDel <=0.15 and SpliceAI <=0.1.
Evidence considered
- BayesDel no-AF score 0.148379
- SpliceAI max delta 0.00
- Residue 1387 is outside ENIGMA BRCA1 clinically important domains
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.481. BayesDel score = 0.148379.
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 / 1,612,348 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/224433/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41242987-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43090970-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.4159…
- OncoKB ↗www.oncokb.org/gene/BRCA1/S1387P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.4159T%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
This variant is present in gnomAD v4.1 (AF= 1.24043e-06; MAF= 0.00012%, 2/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69594e-06; MAF= 0.00017%, 2/1179284 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.02755e-06; MAF= 0.00040%, 1/248290 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89696e-06; MAF= 0.00089%, 1/112398 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Likely Benign 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 = 0.00). REVEL score = 0.481. BayesDel score = 0.148379.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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.