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.1 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).2 A calibrated BRCA1 functional assay reported no damaging effect for p.Ala102Gly, and ENIGMA assigns BS3_Strong for this variant.3 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.4
Final classification
Benign
BS3BP1BP6
BRCA1
c.305C>G
p.Ala102Gly
This variant
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.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (official ClinGen CSPEC/VCEP criteria-combination rules)
Classification rationale
BS3BP1BP6
Benign
BRCA1 c.305C>G
BS3 + BP1 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18PMID:30219179 ↗cspec ↗
4
spliceai ↗vcep_supplementarytables_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
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.
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
BS3
strong
Benign
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).
ENIGMA Table 9: BS3 Strong for c.305C>G p.(Ala102Gly)Reported by one calibrated study to exhibit protein function similar to benign control variantsStarita 2018 functional assay result: no functional impact / 0 depleted
BP1
strong
Benign
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.
Protein consequence p.(Ala102Gly)BRCA1 RING domain defined as aa 2-101Ala102 lies outside the defined RING domain
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
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.
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.
PS3
Available functional evidence does not support a damaging effect.
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.
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.
PM3
No evidence was identified for biallelic BRCA1 variation in a proband with BRCA1-related Fanconi anemia, so PM3 was not assessed.
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.
PP1
No quantitative co-segregation data were identified for affected relatives, so PP1 was not assessed.
PP3
Available predictive evidence does not meet the ENIGMA BRCA1/2 thresholds for PP3.
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.
Benign
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.
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.
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.
BS4
No quantitative evidence for lack of segregation in affected relatives was identified, so BS4 was not assessed.
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.
BP7
No variant-specific mRNA assay showing a normal transcript profile was identified, so BP7 was not assessed.
N/A · 9
PS2 · PM1 · PM4 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00025%
· 4 / 1,609,246
0 hom
0 hom
Remaining individuals 3 / 62,354 |
0.0048% |
African/African American 1 / 74,900 |
0.0013% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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 in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
A Multiplex Homology-Directed DNA Repair Assay Reveals the Impact of More Than 1
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links