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LYFE SCIENCES
Project: HERA
NM_007294.4:c.305C>G
p.Ala102Gly  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗ cspec ↗
2

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).

gnomad_v2 ↗ gnomad_v4 ↗
3

A calibrated BRCA1 functional assay reported no damaging effect for p.Ala102Gly, and ENIGMA assigns BS3_Strong for this variant.

PMID:30219179 ↗ cspec ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA102
Hotspots ↗