The BRCA1 c.4327C>G (p.Arg1443Gly; p.R1443G) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.1 This variant is present in population databases, including gnomAD v2.1 at 9/282760 alleles (AF 3.18291e-05; grpmax FAF 2.294e-05) and gnomAD v4.1 at 65/1613954 alleles (AF 4.02738e-05; grpmax FAF 3.666e-05), which exceeds the BRCA1 BS1 supporting threshold of 0.00002 but remains below the BA1 threshold of 0.001.2 In two calibrated functional studies curated by ENIGMA, this variant showed no functional impact and protein behavior similar to benign control variants, supporting BS3 at strong strength.3 Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.285466, and REVEL is 0.007; because Arg1443 lies outside the BRCA1 ENIGMA clinically important functional domains, this profile supports BP1_Strong rather than PP3.4
BRCA1
Final classification
Benign
BRCA1 c.4327C>G · p.Arg1443Gly
BRCA1
The BRCA1 c.4327C>G (p.Arg1443Gly; p.R1443G) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.
ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework: BS3_Strong and BP1_Strong satisfy the Benign rule requiring at least two strong benign criteria; BS1_Supporting and BP6_Supporting_Benign provide additional benign support.
Classification rationale
BS1BS3BP1BP6
Benign
BRCA1 c.4327C>G
BS1 + BS3 + BP1 + BP6
→
Benign
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
4
spliceai ↗bayesdelrevelcspec ↗vcep_appendices_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 · 4 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= 4.02738e-05; MAF= 0.00403%, 65/1613954 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.33528e-05; MAF= 0.00834%, 5/59986 alleles, homozygotes = 0); grpmax FAF= 3.666e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18291e-05; MAF= 0.00318%, 9/282760 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138581; MAF= 0.01386%, 1/7216 alleles, homozygotes = 0); grpmax FAF= 2.294e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.004%
· 65 / 1,613,954
0 hom · FAF 0.0037%
0 hom · FAF 0.0037%
Admixed American 5 / 59,986 |
0.0083% |
European (non-Finnish) 55 / 1,179,998 |
0.0047% |
African/African American 3 / 74,910 |
0.004% |
Remaining individuals 2 / 62,486 |
0.0032% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0032%
· 9 / 282,760
0 hom · FAF 0.0023%
0 hom · FAF 0.0023%
Remaining individuals 1 / 7,216 |
0.014% |
Admixed American 2 / 35,428 |
0.0056% |
European (non-Finnish) 6 / 129,108 |
0.0046% |
+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (6 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.007. BayesDel score = -0.285466.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
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
2papers 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:30765603
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
PMID PMID:32546644
Found
Structured finding pending for this record — see source link.
Applied to
→BS3 supports · met
Sources & reference links