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
BRCA1
Final classification
Benign
BRCA1 c.305C>G · p.Ala102Gly
BRCA1
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
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
PMID PMID:30219179
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links