About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.32T>G, p.(Val11Gly)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Strong
PS3 · strong
In a calibrated functional study summarized by the ENIGMA BRCA1 specification, this variant showed loss of function with complete functional impact and behaved similarly to pathogenic control variants, supporting a damaging effect on BRCA1 protein function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength in the reviewed evidence.
PP3Supporting
PP3 · supporting
This missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain. BayesDel no-AF is 0.325211, which is above the ENIGMA PP3 threshold of 0.28, and REVEL is 0.753, supporting a damaging protein effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
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 final-classification framework (Table 3 adapted ACMG/AMP criteria-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
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
4 reported laboratory submissions
3 Uncertain significance · 1 Likely pathogenic.
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
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.
28 criteria with recorded statuses: 4 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
The BRCA1 c.32T>G (p.(Val11Gly)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a Likely Pathogenic expert-panel classification from ClinGen ENIGMA with additional conflicting submissions.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases consistent with PM2_Supporting.
In calibrated functional data, this variant showed complete functional impact with loss of function and was summarized by the ENIGMA BRCA1 specification as meeting PS3_Strong.
This missense change is located in the BRCA1 RING domain, with BayesDel no-AF 0.325211 above the ENIGMA PP3 threshold of 0.28 and REVEL 0.753, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.00; these findings support PP3 and do not support BP4.
No criteria match.
Met · 4
PS3 StrongIn a calibrated functional study summarized by the ENIGMA BRCA1 specification, this variant showed loss of function with complete functional impact and behaved similarly to pathogenic control variants, supporting a damaging effect on BRCA1 protein function. Details ▾Hide ▴
Rule
ENIGMA BRCA1 Table 9 assigns PS3 strength from calibrated functional assays.
Evidence considered
- Table 9: c.32T>G p.(Val11Gly) assigned PS3 Strong
- ST4: Functional impact - complete
- LOF
- Findlay 2018 saturation genome editing
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, supporting rarity in population databases and meeting PM2 at supporting strength in the reviewed evidence. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM2 is applied at Supporting strength for absence from population controls.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Still missing
- The ENIGMA PM2 rule cites gnomAD v2.1 and v3.1
- v3.1 was not separately reviewed in the retrieved materials.
Sources
PP3 SupportingThis missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain. BayesDel no-AF is 0.325211, which is above the ENIGMA PP3 threshold of 0.28, and REVEL is 0.753, supporting a damaging protein effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 applies to missense variants in key domains with BayesDel no-AF score ≥0.28, or to predicted splice-impact variants with SpliceAI ≥0.2.
Evidence considered
- RING domain location at codon 11
- BayesDel no-AF 0.325211
- REVEL 0.753
- SpliceAI max delta 0.00
Sources
PP5 SupportingExpert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PP4 The BRCA1 clinical-history likelihood ratio for this variant is 1.0618 based on 1 proband, which is below the ENIGMA PP4 supporting threshold of 2.08. This value is in the neutral zone and does not support PP4. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP4 requires a multifactorial clinical-data LR ≥2.08 for Supporting strength.
Evidence considered
- Clinical-history LR 1.061794714953085
- N probands = 1
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore well below the ENIGMA BA1 stand-alone threshold of filter allele frequency greater than 0.1%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BA1 requires filter allele frequency >0.1%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the ENIGMA BS1 population thresholds above 0.002% or 0.01%. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS1 requires filter allele frequency above the specified benign thresholds.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS3 Available functional evidence does not show a normal or non-damaging effect. Instead, calibrated functional data show complete loss of function, so BS3 is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS3 requires well-established studies showing no damaging effect on protein function.
Evidence considered
- Table 9 assigns PS3 Strong
- not BS3
- ST4 shows complete functional impact / LOF
Sources
BP1 This missense variant is located at codon 11 within the BRCA1 RING domain (aa 2-101), so it is not outside a clinically important functional domain. BP1_Strong therefore does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP1_Strong applies only to missense or similar variants outside clinically important functional domains with no predicted splice impact.
Evidence considered
- Codon 11 lies in BRCA1 RING domain
- SpliceAI max delta 0.00
Sources
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, BP4 is not met because this missense variant is in the BRCA1 RING domain and BayesDel no-AF is 0.325211, which is above the benign threshold of 0.15 rather than at or below it. REVEL is also elevated at 0.753. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants in key domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- RING domain location
- BayesDel no-AF 0.325211
- SpliceAI max delta 0.00
- REVEL 0.753
Sources
BP5 The BRCA1 clinical-history likelihood ratio for this variant is 1.0618 based on 1 proband, which is above the ENIGMA BP5 supporting threshold of 0.48. This value is in the neutral zone and does not support BP5. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP5 requires a multifactorial clinical-data LR ≤0.48 for Supporting strength.
Evidence considered
- Clinical-history LR 1.061794714953085
- N probands = 1
Sources
Not assessed · 6 · no assessment recorded
PS1 No same-amino-acid pathogenic comparator or same-splicing-impact pathogenic comparator was identified in the reviewed materials, so PS1 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS1 requires a previously classified pathogenic or likely pathogenic comparator with the same protein or splicing effect.
Evidence considered
- No verified pathogenic same-amino-acid or same-splice comparator identified
Still missing
- A dedicated PS1 comparator search was not confirmed in the reviewed materials.
Sources
PS4 No case-control study or quantified enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls, so PS4 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PS4 requires significant enrichment in affected individuals compared with controls.
Evidence considered
- No qualifying prevalence study identified
Still missing
- No odds ratio
- confidence interval
- or affected-versus-control count was identified for this variant.
Sources
PM3 No evidence was identified that this variant was observed with a second BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM3 is reserved for BRCA1/2-related Fanconi anemia contexts.
Evidence considered
- No qualifying recessive disease evidence identified
Still missing
- No Fanconi anemia proband data or trans observations were identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP1 requires quantitative cosegregation evidence.
Evidence considered
- No segregation evidence identified
Still missing
- No pedigree-based likelihood ratio or quantified cosegregation study was identified.
Sources
BS2 No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2, so BS2 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS2 uses a point-based framework in the absence of recessive disease features.
Evidence considered
- No BS2 evidence identified
Still missing
- No qualifying proband-level BS2 point data were identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 was not established. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BS4 requires quantitative evidence for lack of segregation in affected relatives.
Evidence considered
- No non-segregation evidence identified
Still missing
- No quantitative lack-of-segregation likelihood ratio was identified.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Val11Gly), and does not fall into the BRCA1 null-variant categories used for PVS1 such as nonsense, frameshift, initiation codon, or canonical ±1,2 splice-site change. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PVS1 applies to null variants or qualifying RNA evidence, not to this missense substitution.
Evidence considered
- Missense variant p.(Val11Gly)
- Generic PVS1 scaffold excludes this variant from default null-variant buckets
Sources
PS2 VCEPThis criterion is not used in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
VCEP rule
PS2 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks PS2 not applicable
Sources
PM1 VCEPPM1 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
PM1 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks PM1 not applicable
Sources
PM4 VCEPPM4 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
PM4 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks PM4 not applicable
Sources
PM5 N/AFor BRCA1, PM5 is repurposed for protein-truncating variants in eligible exons rather than classic same-residue missense logic. This variant is a missense substitution, so PM5 does not apply. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PM5 applies to qualifying protein-termination variants, not this missense change.
Evidence considered
- PM5 mode is PTC-specific in BRCA1
- Variant is missense
- not truncating
Sources
PM6 VCEPThis criterion is not used in the ENIGMA BRCA1 framework for this review. Details ▾Hide ▴
VCEP rule
PM6 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks PM6 not applicable
Sources
PP2 VCEPPP2 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
PP2 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks PP2 not applicable
Sources
BP2 VCEPBP2 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
BP2 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks BP2 not applicable
Sources
BP3 VCEPBP3 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
BP3 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks BP3 not applicable
Sources
BP6 VCEPBP6 is not applied in the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
VCEP rule
BP6 marked not applicable by ENIGMA BRCA1 specification.
Evidence considered
- CSPEC marks BP6 not applicable
Sources
BP7 N/ABP7 in this framework is used for silent or intronic variants, or RNA evidence contexts, and does not apply to this missense substitution. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 is directed to silent, intronic, or RNA-based evidence contexts.
Evidence considered
- Variant is missense
- not silent or intronic
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.3
- Coding (HGVS c.)
- NM_007294.3:c.32T>G
- Protein (HGVS p.)
- NP_009225.1:p.(Val11Gly)
- GRCh38
- chr17:43124065 A>C
- GRCh37
- chr17:41276082 A>C
- ClinVar
- 1738154, 245973
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
—
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.753
- BayesDel
- 0.325
How the predictions were used
PP3 SupportingThis missense variant lies in the BRCA1 RING domain (aa 2-101), a clinically important functional domain. BayesDel no-AF is 0.325211, which is above the ENIGMA PP3 threshold of 0.28, and REVEL is 0.753, supporting a damaging protein effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ENIGMA BRCA1 PP3 applies to missense variants in key domains with BayesDel no-AF score ≥0.28, or to predicted splice-impact variants with SpliceAI ≥0.2.
Evidence considered
- RING domain location at codon 11
- BayesDel no-AF 0.325211
- REVEL 0.753
- SpliceAI max delta 0.00
Sources
BP4 Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, BP4 is not met because this missense variant is in the BRCA1 RING domain and BayesDel no-AF is 0.325211, which is above the benign threshold of 0.15 rather than at or below it. REVEL is also elevated at 0.753. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP4 for missense variants in key domains requires BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
Evidence considered
- RING domain location
- BayesDel no-AF 0.325211
- SpliceAI max delta 0.00
- REVEL 0.753
Sources
BP7 N/ABP7 in this framework is used for silent or intronic variants, or RNA evidence contexts, and does not apply to this missense substitution. Details ▾Hide ▴
Rule
ENIGMA BRCA1 BP7 is directed to silent, intronic, or RNA-based evidence contexts.
Evidence considered
- Variant is missense
- not silent or intronic
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.753. BayesDel score = 0.325211.
9 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 18493658 ↗Re-engineering a split-GFP reassembly screen to examine RING-domain interactions between BARD1 and BRCA1 mutants observed in cancer patients.No paper-specific finding is recorded.
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
-
PMID 30209399 ↗Accurate classification of BRCA1 variants with saturation genome editing.Findlay GM et al. · 2018No paper-specific finding is recorded.
-
PMID 30219179 ↗A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1,000 BRCA1 Missense Substitution Variants on Protein Function.Starita LM et al. · 2018No paper-specific finding is recorded.
-
PMID 30702160 ↗Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.Bhaskaran SP et al. · 2019No paper-specific finding is recorded.
-
PMID 31853058 ↗Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.Li H et al. · 2020No paper-specific finding is recorded.
-
PMID 31911673 ↗Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".Dines JN et al. · 2020No paper-specific finding is recorded.
-
PMID 32377563 ↗Prediction of the functional impact of missense variants in BRCA1 and BRCA2 with BRCA-ML.No paper-specific finding is recorded.
-
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
3 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/245973/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41276082-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43124065-A-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.3%3Ac.32T%…
- OncoKB ↗www.oncokb.org/gene/BRCA1/V11G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.32T%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 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). (ClinVarID = 245973)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.753. BayesDel score = 0.325211.
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.