About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.305C>G, p.(Ala102Gly)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS3Strong
BS3 · strong
A calibrated BRCA1 functional study found no damaging effect for p.(Ala102Gly). ENIGMA Table 9 assigns BS3_Strong based on one calibrated study showing protein function similar to benign control variants (PMID:30219179).
BP1Strong
BP1 · strong
This is a missense variant located just outside the BRCA1 clinically important RING domain, which is defined as amino acids 2-101, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the 0.1 threshold. This meets ENIGMA BP1_Strong for a missense variant outside a clinically important domain without predicted splice disruption.
BP6Supporting
BP6 · supporting
Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official ClinGen CSPEC/VCEP 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
4 / 1,609,246 alleles
gnomAD v4.1: 4 / 1,609,246 alleles. Recorded AF 2.48564e-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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 · 8 not met · 8 not assessed · 9 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.305C>G (p.Ala102Gly) variant has been reported in ClinVar and includes a Benign expert-panel classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 at AF 2.49e-06 (4/1609246 alleles), with a highest observed subpopulation AF of 4.81e-05 (3/62354 alleles).
A calibrated BRCA1 functional assay reported no damaging effect for p.Ala102Gly, and ENIGMA assigns BS3_Strong for this variant.
SpliceAI predicts no significant splice impact with a max delta score of 0.01, and the ENIGMA BRCA1 bioinformatic dataset reports BayesDel 0.14; together with the variant's position outside the BRCA1 RING domain (aa 2-101), this supports a benign missense interpretation.
No criteria match.
Met · 3
BS3 StrongA calibrated BRCA1 functional study found no damaging effect for p.(Ala102Gly). ENIGMA Table 9 assigns BS3_Strong based on one calibrated study showing protein function similar to benign control variants (PMID:30219179). Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BS3_Strong
Evidence considered
- ENIGMA Table 9: BS3 Strong for c.305C>G p.(Ala102Gly)
- Reported by one calibrated study to exhibit protein function similar to benign control variants
- Starita 2018 functional assay result: no functional impact / 0 depleted
Sources
BP1 StrongThis is a missense variant located just outside the BRCA1 clinically important RING domain, which is defined as amino acids 2-101, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the 0.1 threshold. This meets ENIGMA BP1_Strong for a missense variant outside a clinically important domain without predicted splice disruption. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP1_Strong
Evidence considered
- Protein consequence p.(Ala102Gly)
- BRCA1 RING domain defined as aa 2-101
- Ala102 lies outside the defined RING domain
- SpliceAI max delta score 0.01
Sources
Not met · 8 · evaluated, threshold not reached
PVS1 This missense variant does not create a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or exon-level loss-of-function event, so the BRCA1 PVS1 rule is not met. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 PVS1 applies to null variants at appropriate strength; this variant is not a null variant.
Evidence considered
- NM_007294.4:c.305C>G is a missense variant with protein consequence p.(Ala102Gly)
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
- BRCA1 loss of function is an established disease mechanism
- but this variant is not a loss-of-function variant
Sources
PS3 Available functional evidence does not support a damaging effect. A calibrated BRCA1 functional study reported no functional impact for p.(Ala102Gly), so PS3 is not met. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 lists c.305C>G p.(Ala102Gly) under BS3 Strong rather than PS3
- Starita 2018 functional assay reported no depletion / no damaging functional effect
Sources
vcep_specifications_table9_v1_2_2024_11_18PMID:30219179 ↗
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 2.49e-06 (4/1609246 alleles; highest subpopulation AF 4.81e-05, 3/62354), so it is not absent from population databases and PM2 is not applied. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 2.4856361302125345e-06
- Highest observed subpopulation AF 4.811239054431151e-05 in Remaining individuals
Sources
PP3 Available predictive evidence does not meet the ENIGMA BRCA1/2 thresholds for PP3. SpliceAI predicts no significant splice effect with a max delta score of 0.01, which is below the 0.2 threshold, and the ENIGMA bioinformatic dataset reports BayesDel 0.14, which is below the 0.28 threshold for pathogenic computational support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Supplementary Table 11 BayesDel 0.14 for c.305C>G
- ENIGMA PP3 requires SpliceAI >=0.2 for splice prediction or BayesDel >=0.28 for eligible missense variants in clinically important domains
Sources
PP4 The BRCA1 clinical-history likelihood ratio for this variant is 0.688 in 2 probands, which is below the ENIGMA PP4 supporting threshold of 2.08, so PP4 is not met. Details ▾Hide ▴
Evidence considered
- Clinical-history LR 0.6878619505200587
- N probands 2
- PP4 thresholds: Supporting >=2.08
- Moderate >=4.3
- Strong >=18.7
Sources
BA1 This variant does not meet BA1 because it is absent from gnomAD v2.1 and its observed gnomAD v4.1 frequency is 2.49e-06, which is far below the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 2.4856361302125345e-06
- BA1 threshold FAF >0.001
Sources
BS1 This variant does not meet BS1 because it is absent from gnomAD v2.1 and its highest observed gnomAD v4.1 subpopulation frequency is 4.81e-05, which is above the BS1 supporting threshold of 2e-05 but below the BS1 strong threshold of 1e-04; however the ENIGMA BS1 rule is defined using filter allele frequency in gnomAD v2.1 and/or v3.1, and no qualifying FAF evidence was identified. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 highest observed subpopulation AF 4.811239054431151e-05
- ENIGMA BS1 uses FAF thresholds in gnomAD v2.1 and/or v3.1
Still missing
- A qualifying non-founder population filter allele frequency from the ENIGMA-specified datasets would be needed to apply BS1.
Sources
BP5 The BRCA1 clinical-history likelihood ratio for this variant is 0.688 in 2 probands, which is above the ENIGMA BP5 supporting threshold of 0.48, so BP5 is not met. Details ▾Hide ▴
Evidence considered
- Clinical-history LR 0.6878619505200587
- N probands 2
- BP5 thresholds: Supporting <=0.48
- Moderate <=0.23
- Strong <=0.05
Sources
Not assessed · 8 · no assessment recorded
PS1 No evidence was identified showing that this variant causes the same protein or splicing consequence as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1/2 PS1 requires equivalence to a previously classified pathogenic or likely pathogenic variant
Still missing
- A curated codon-level or splice-equivalence comparison set would be needed to evaluate PS1.
Sources
PS4 No case-control study or other quantitative prevalence data were identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed. Details ▾Hide ▴
PM3 No evidence was identified for biallelic BRCA1 variation in a proband with BRCA1-related Fanconi anemia, so PM3 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1/2 PM3 is limited to BRCA1/2-related Fanconi anemia contexts
Still missing
- Fanconi-anemia phenotype and phase data would be needed to evaluate PM3.
Sources
PM5 The ENIGMA BRCA1/2 PM5 rule is mainly used for protein-truncating variants in eligible exons, and no qualifying codon-level pathogenic comparator was identified for this missense variant, so PM5 was not assessed. Details ▾Hide ▴
Evidence considered
- This variant is missense
- not a protein-truncating variant
- No codon-level PM5 comparator was identified in reviewed ENIGMA materials
Still missing
- A curated codon-level comparison demonstrating an eligible PM5 scenario would be needed.
Sources
PP1 No quantitative co-segregation data were identified for affected relatives, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1/2 PP1 requires quantitative segregation evidence
Still missing
- Family segregation data with likelihood-ratio analysis would be needed to evaluate PP1.
Sources
BS2 No data were identified showing this variant in individuals evaluated for absence of BRCA1-related Fanconi anemia features under the ENIGMA point-based BS2 framework, so BS2 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1/2 BS2 requires point-based evidence in the absence of recessive disease features
Still missing
- Point-based unaffected or non-Fanconi-anemia evidence would be needed to evaluate BS2.
Sources
BS4 No quantitative evidence for lack of segregation in affected relatives was identified, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1/2 BS4 requires quantitative lack-of-segregation evidence
Still missing
- Family non-segregation data with likelihood-ratio analysis would be needed to evaluate BS4.
Sources
BP7 No variant-specific mRNA assay showing a normal transcript profile was identified, so BP7 was not assessed. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no significant splice impact
- ENIGMA BP7 requires defined RNA evidence or specific silent/intronic contexts
Still missing
- A qualifying RNA study would be needed to evaluate BP7.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 N/ADe novo evidence is not part of the ENIGMA BRCA1/2 framework for this gene, so PS2 is not applicable. Details ▾Hide ▴
PM1 N/APM1 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
PM4 N/APM4 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
PM6 N/APM6 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
BP2 N/ABP2 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the ENIGMA BRCA1/2 framework. Details ▾Hide ▴
BP4 N/AFor BRCA1 missense variants, BP4 applies within a clinically important functional domain when BayesDel is 0.15 or less and SpliceAI is 0.1 or less. This variant is outside the BRCA1 clinically important domains, so BP4 is not the applicable benign bioinformatic rule. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Ala102Gly)
- Variant lies outside the BRCA1 RING domain defined as aa 2-101
- SpliceAI max delta score 0.01
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.305C>G
- Protein (HGVS p.)
- NP_009225.1:p.(Ala102Gly)
- GRCh38
- chr17:43104258 G>C
- GRCh37
- chr17:41256275 G>C
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
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
4 / 1,609,246 alleles
AF 2.49e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,609,246 alleles · 0 hom
| Remaining individuals3 / 62,354 | 4.8e-05 |
| African/African American1 / 74,900 | 1.3e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.48564e-06; MAF= 0.00025%, 4/1609246 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.81124e-05; MAF= 0.00481%, 3/62354 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Available predictive evidence does not meet the ENIGMA BRCA1/2 thresholds for PP3. SpliceAI predicts no significant splice effect with a max delta score of 0.01, which is below the 0.2 threshold, and the ENIGMA bioinformatic dataset reports BayesDel 0.14, which is below the 0.28 threshold for pathogenic computational support. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- Supplementary Table 11 BayesDel 0.14 for c.305C>G
- ENIGMA PP3 requires SpliceAI >=0.2 for splice prediction or BayesDel >=0.28 for eligible missense variants in clinically important domains
Sources
BP7 No variant-specific mRNA assay showing a normal transcript profile was identified, so BP7 was not assessed. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no significant splice impact
- ENIGMA BP7 requires defined RNA evidence or specific silent/intronic contexts
Still missing
- A qualifying RNA study would be needed to evaluate BP7.
Sources
BP4 N/AFor BRCA1 missense variants, BP4 applies within a clinically important functional domain when BayesDel is 0.15 or less and SpliceAI is 0.1 or less. This variant is outside the BRCA1 clinically important domains, so BP4 is not the applicable benign bioinformatic rule. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Ala102Gly)
- Variant lies outside the BRCA1 RING domain defined as aa 2-101
- SpliceAI max delta score 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
4 / 1,609,246 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/37505/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41256275-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43104258-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.305C…
- OncoKB ↗www.oncokb.org/gene/BRCA1/A102G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.305C%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= 2.48564e-06; MAF= 0.00025%, 4/1609246 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.81124e-05; MAF= 0.00481%, 3/62354 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory) and as 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 = 0.01).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.