About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.101C>T, p.(Pro34Leu)
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
In the ENIGMA BRCA1 functional evidence table, this exact variant is assigned PS3_Strong based on a calibrated functional study. The cited study reported loss-of-function/complete functional impact for c.101C>T (p.Pro34Leu), supporting a damaging effect on BRCA1 function.
PP3Supporting
PP3 · supporting
This missense variant lies in the BRCA1 RING domain, a clinically important functional domain, and BayesDel is 0.450189, which is above the ENIGMA PP3 threshold of 0.28. REVEL is also high at 0.837, while SpliceAI predicts no significant splice impact (max delta score 0.01), supporting a damaging protein effect rather than a splice-driven mechanism.
PP5Supporting
PP5 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 Table 3 final-classification framework
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
5 / 1,613,658 alleles
gnomAD v4.1: 5 / 1,613,658 alleles. Recorded AF 3.09855e-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 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.
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: 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.101C>T (p.Pro34Leu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as Likely Pathogenic.
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (5/1,613,658 alleles; AF 3.10e-06; grpmax FAF 1.24e-06).
In a calibrated BRCA1 functional study summarized by the ENIGMA BRCA1 specification, c.101C>T (p.Pro34Leu) showed loss of function/complete functional impact, supporting PS3_Strong.
This missense change is located in the BRCA1 RING domain; BayesDel is 0.450189, above the ENIGMA PP3 threshold of 0.28, REVEL is 0.837, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a damaging protein effect without predicted splice disruption.
No criteria match.
Met · 3
PS3 StrongIn the ENIGMA BRCA1 functional evidence table, this exact variant is assigned PS3_Strong based on a calibrated functional study. The cited study reported loss-of-function/complete functional impact for c.101C>T (p.Pro34Leu), supporting a damaging effect on BRCA1 function. Details ▾Hide ▴
Rule
Apply PS3 for well-established functional studies showing a damaging effect; use Table 9 for calibrated code recommendations.
Evidence considered
- ENIGMA Table 9 lists BRCA1 c.101C>T p.(Pro34Leu) as PS3 Strong.
- Table 9 cites Findlay 2018 as the supporting calibrated study.
Sources
PP3 SupportingThis missense variant lies in the BRCA1 RING domain, a clinically important functional domain, and BayesDel is 0.450189, which is above the ENIGMA PP3 threshold of 0.28. REVEL is also high at 0.837, while SpliceAI predicts no significant splice impact (max delta score 0.01), supporting a damaging protein effect rather than a splice-driven mechanism. Details ▾Hide ▴
Rule
ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.28, or to variants with predicted splice impact meeting threshold.
Evidence considered
- BRCA1 RING domain spans amino acids 2-101.
- BayesDel score 0.450189.
- REVEL score 0.837.
- SpliceAI max delta score 0.01.
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 6 · evaluated, threshold not reached
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 5/1,613,658 alleles (AF 3.10e-06; grpmax FAF 1.24e-06). The available control data therefore do not establish the ENIGMA requirement for absence from controls, so PM2 was not applied. Details ▾Hide ▴
Rule
ENIGMA PM2_Supporting requires absence from controls in specified gnomAD datasets.
Evidence considered
- gnomAD v2.1 absent.
- gnomAD v4.1 total AF 3.09855e-06 with 5 alleles and 0 homozygotes.
Still missing
- No gnomAD v3.1-specific result was identified in the reviewed materials.
Sources
BA1 The highest available population filter allele frequency is far below the ENIGMA BA1 threshold of greater than 0.1%. In gnomAD v4.1, the grpmax FAF is 1.24e-06, so BA1 is not met. Details ▾Hide ▴
Rule
ENIGMA BA1 requires FAF >0.001 in an appropriate population dataset.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06.
Sources
BS1 The available population frequency is below ENIGMA BS1 thresholds. The highest available grpmax FAF is 1.24e-06, which is below both the BS1_Supporting threshold of greater than 0.00002 and the BS1 threshold of greater than 0.0001. Details ▾Hide ▴
Rule
ENIGMA BS1 requires FAF >0.00002 for Supporting or >0.0001 for Strong.
Evidence considered
- gnomAD v4.1 grpmax FAF 1.24e-06.
Sources
BS3 Available functional evidence does not show a benign or neutral effect. Instead, the ENIGMA BRCA1 functional evidence table assigns this exact variant PS3_Strong for damaging loss of function, so BS3 is not met. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect.
Evidence considered
- ENIGMA Table 9 assigns PS3 Strong
- not BS3
- to c.101C>T p.(Pro34Leu).
Sources
BP1 This missense variant is located in the BRCA1 RING domain (amino acids 2-101), which is a clinically important functional domain. The ENIGMA BP1_Strong rule applies only to missense or similar variants outside such domains with no predicted splice impact, so BP1 is not met. Details ▾Hide ▴
Rule
ENIGMA BP1_Strong applies outside clinically important domains when no splice impact is predicted.
Evidence considered
- BRCA1 RING domain definition.
- SpliceAI max delta score 0.01.
Sources
BP4 This variant does not meet the ENIGMA BP4 rule because BayesDel is 0.450189, which is above the benign threshold of 0.15, although SpliceAI predicts no significant splice impact (max delta score 0.01). The computational evidence therefore does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BP4 for missense variants in functional domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- BayesDel score 0.450189.
- SpliceAI max delta score 0.01.
Sources
Not assessed · 8 · no assessment recorded
PS1 No validated evidence was identified showing that this variant produces the same amino acid or splice consequence as a different previously established pathogenic BRCA1 variant, so PS1 was not assessed. Details ▾Hide ▴
Rule
ENIGMA PS1 requires the same protein or splice consequence as a previously classified pathogenic variant.
Evidence considered
- ClinVar summary for this exact variant was reviewed.
- ENIGMA PS1 requires a previously established pathogenic comparator variant with the same protein or splice consequence.
Still missing
- No exact same-amino-acid or same-splice reference variant evidence was identified in the reviewed materials.
Sources
PS4 No case-control study, odds ratio, or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- ClinVar observation data were reviewed.
- No PS4-level enrichment data were identified in the reviewed materials.
Still missing
- No affected-versus-control comparison with OR and confidence interval was identified.
- No variant-specific case-control dataset was identified.
Sources
PM3 No evidence was identified for co-occurrence with another BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Rule
ENIGMA PM3 is used only for biallelic BRCA1/2 Fanconi anemia contexts.
Evidence considered
- ENIGMA PM3 is restricted to BRCA1/2-related Fanconi anemia evidence.
Still missing
- No Fanconi anemia phenotype data were identified.
- No phase-confirmed second BRCA1 variant evidence was identified.
Sources
PP1 No segregation data were identified for this variant, and no quantitative co-segregation likelihood ratio was available, so PP1 was not assessed. Details ▾Hide ▴
PP4 No variant-level personal or family history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA PP4 uses multifactorial clinical likelihood ratios, with Supporting at LR ≥2.08.
Evidence considered
- Reviewed BRCA1 clinical-history LR resource
- no exact variant match was identified.
Still missing
- No exact c.101C>T row was identified in the BRCA1 clinical-history likelihood-ratio table.
- No multifactorial LR ≥2.08 was identified.
Sources
BS2 No data were identified showing the variant in individuals without features of BRCA1-related Fanconi anemia at a level that would satisfy the ENIGMA point-based BS2 framework, so BS2 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BS2 uses point-based evidence from individuals lacking Fanconi anemia features.
Evidence considered
- ENIGMA BS2 is based on proband points in the absence of recessive disease features.
Still missing
- No BS2 point-based proband evidence was identified.
Sources
BS4 No lack-of-segregation data or quantitative segregation likelihood ratio against pathogenicity was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BS4 requires quantitative evidence for lack of segregation in affected family members.
Evidence considered
- Reviewed multifactorial and legacy segregation resources
- no exact BS4-supporting evidence was identified.
Still missing
- No non-segregation pedigree data were identified.
- No segregation LR ≤0.48 was identified.
Sources
BP5 No variant-level multifactorial clinical likelihood ratio against pathogenicity was identified for this variant, so BP5 was not assessed. Details ▾Hide ▴
Rule
ENIGMA BP5 uses multifactorial clinical likelihood ratios, with Supporting at LR ≤0.48.
Evidence considered
- Reviewed BRCA1 clinical-history LR resource
- no exact variant match was identified.
Still missing
- No exact c.101C>T row was identified in the BRCA1 clinical-history likelihood-ratio table.
- No multifactorial LR ≤0.48 was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not fall into the BRCA1/ENIGMA PVS1 null-variant categories, and SpliceAI does not predict a splice effect (max delta score 0.01). Available evidence therefore does not support applying PVS1. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 applies to null variants or RNA evidence meeting PVS1 (RNA) guidance; this variant does not meet those entry criteria.
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the ENIGMA framework.
- Variant-level PVS1 scaffold identifies this change as outside nonsense
- frameshift
- and canonical ±1
- 2 splice categories.
- SpliceAI max delta score 0.01.
Sources
PS2 N/ADe novo evidence is not used for BRCA1 in this ENIGMA framework, so PS2 is not applicable. Details ▾Hide ▴
Rule
PS2 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists PS2 as not applicable for this framework.
Sources
PM1 N/APM1 is designated not applicable in the ENIGMA BRCA1 specification and was not used for this variant. Details ▾Hide ▴
Rule
PM1 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PM1 as not applicable.
Sources
PM4 N/APM4 is designated not applicable in the ENIGMA BRCA1 specification and was not used for this missense variant. Details ▾Hide ▴
Rule
PM4 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC marks PM4 as not applicable.
Sources
PM5 N/AIn the ENIGMA BRCA1 specification, PM5 is used here as a protein-truncating-code criterion for PTC variants with exon-specific weighting. This missense variant does not meet that variant-type requirement, so PM5 was not applied. Details ▾Hide ▴
Rule
ENIGMA PM5 in this BRCA1 framework is applied as PM5_PTC for qualifying truncating variants.
Evidence considered
- ENIGMA Table 4 provides exon-specific PM5_PTC guidance for truncating variants.
- This variant is missense
- p.(Pro34Leu).
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
PM6 N/APM6 is not used in this ENIGMA BRCA1 framework, so it is not applicable. Details ▾Hide ▴
Rule
PM6 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists PM6 as not applicable.
Sources
PP2 N/APP2 is not used in the ENIGMA BRCA1 specification and is not applicable. Details ▾Hide ▴
Rule
PP2 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists PP2 as not applicable.
Sources
BP2 N/ABP2 is not used in the ENIGMA BRCA1 specification and is not applicable. Details ▾Hide ▴
Rule
BP2 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists BP2 as not applicable.
Sources
BP3 N/ABP3 is not used in the ENIGMA BRCA1 specification and is not applicable. Details ▾Hide ▴
Rule
BP3 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists BP3 as not applicable.
Sources
BP6 N/ABP6 is not used in the ENIGMA BRCA1 specification and is not applicable. Details ▾Hide ▴
Rule
BP6 not applicable in ENIGMA BRCA1/2 specification.
Evidence considered
- CSPEC lists BP6 as not applicable.
Sources
BP7 N/AThis is a missense variant in the BRCA1 RING domain, not a silent or intronic variant, and no benign RNA assay evidence was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7 is for qualifying RNA-only, silent, intronic, or selected missense contexts with benign transcript evidence.
Evidence considered
- Variant consequence is missense p.(Pro34Leu).
- SpliceAI max delta score 0.01.
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.101C>T
- Protein (HGVS p.)
- NP_009225.1:p.(Pro34Leu)
- GRCh38
- chr17:43115759 G>A
- GRCh37
- chr17:41267776 G>A
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
5 / 1,613,658 alleles
AF 3.1e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,613,658 alleles · 0 hom · FAF 1.2e-06
| European (non-Finnish)5 / 1,179,798 | 4.2e-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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.09855e-06; MAF= 0.00031%, 5/1613658 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23801e-06; MAF= 0.00042%, 5/1179798 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
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, a clinically important functional domain, and BayesDel is 0.450189, which is above the ENIGMA PP3 threshold of 0.28. REVEL is also high at 0.837, while SpliceAI predicts no significant splice impact (max delta score 0.01), supporting a damaging protein effect rather than a splice-driven mechanism. Details ▾Hide ▴
Rule
ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel no-AF ≥0.28, or to variants with predicted splice impact meeting threshold.
Evidence considered
- BRCA1 RING domain spans amino acids 2-101.
- BayesDel score 0.450189.
- REVEL score 0.837.
- SpliceAI max delta score 0.01.
Sources
BP4 This variant does not meet the ENIGMA BP4 rule because BayesDel is 0.450189, which is above the benign threshold of 0.15, although SpliceAI predicts no significant splice impact (max delta score 0.01). The computational evidence therefore does not support a benign interpretation. Details ▾Hide ▴
Rule
ENIGMA BP4 for missense variants in functional domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- BayesDel score 0.450189.
- SpliceAI max delta score 0.01.
Sources
BP7 N/AThis is a missense variant in the BRCA1 RING domain, not a silent or intronic variant, and no benign RNA assay evidence was identified. BP7 is therefore not applicable. Details ▾Hide ▴
Rule
ENIGMA BP7 is for qualifying RNA-only, silent, intronic, or selected missense contexts with benign transcript evidence.
Evidence considered
- Variant consequence is missense p.(Pro34Leu).
- SpliceAI max delta score 0.01.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.837. BayesDel score = 0.450189.
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
5 / 1,613,658 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/186913/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41267776-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43115759-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.101C…
- OncoKB ↗www.oncokb.org/gene/BRCA1/P34L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.101C%3ET
- 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= 3.09855e-06; MAF= 0.00031%, 5/1613658 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23801e-06; MAF= 0.00042%, 5/1179798 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic 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 = 0.01). REVEL score = 0.837. BayesDel score = 0.450189.
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.