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
Final classification
Benign
BS1BS3BP1BP6
BRCA1
c.4327C>G
p.Arg1443Gly
This variant
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
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 · 4 applied · 14 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 · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
supporting
Benign
The population frequency exceeds the BRCA1 BS1 supporting threshold of greater than 0.00002 but does not exceed the strong threshold of greater than 0.0001. The grpmax FAF is 2.294e-05 in gnomAD v2.1 and 3.666e-05 in gnomAD v4.1, supporting BS1 at supporting strength.
gnomAD v2.1 grpmax FAF 2.294e-05gnomAD v4.1 grpmax FAF 3.666e-05
BS3
strong
Benign
In two calibrated functional studies curated by ENIGMA, this variant showed protein function similar to benign control variants and no functional impact, supporting BS3 at strong strength.
ENIGMA Table 9: BS3 Strong for c.4327C>G p.(Arg1443Gly)Supplementary Table 4: no functional impact
BP1
strong
Benign
This missense variant lies outside the BRCA1 clinically important functional domains defined by ENIGMA, and no splice effect is predicted. Arg1443 is outside the RING domain (aa 2-101), the coiled-coil domain (aa 1391-1424), and the BRCT repeats (aa 1650-1857), and SpliceAI shows a max delta score of 0.01, supporting BP1 at strong strength. REVEL is also low at 0.007.
Residue 1443 is outside ENIGMA BRCA1 functional domainsSpliceAI max delta score 0.01REVEL 0.007
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
PS1
No reviewed evidence established a previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same proven splice effect, so PS1 was not assessed.
PS3
Available functional evidence does not support a damaging effect.
PS4
No case-control study or other reviewed dataset showed a significant enrichment of this variant in affected individuals compared with controls, so PS4 was not assessed.
PM2
This variant is not absent from population databases.
PM3
No reviewed evidence showed this variant in a patient with BRCA1-related Fanconi anemia and an informative co-occurring BRCA1 variant, so PM3 was not assessed.
PP1
No segregation analysis with a quantitative likelihood ratio was identified for this variant, so PP1 was not assessed.
PP3
Computational evidence does not support a damaging effect.
PP4
No variant-specific clinical-history likelihood ratio meeting the BRCA1 ENIGMA PP4 thresholds was identified in the reviewed materials, so PP4 was not assessed.
Benign
BA1
The filter allele frequency does not reach the BRCA1 BA1 threshold of greater than 0.001.
BS2
No reviewed proband data were available to assign BS2 points based on absence of Fanconi anemia features, so BS2 was not assessed.
BS4
No quantitative non-segregation study or other reviewed pedigree evidence arguing against disease segregation was identified, so BS4 was not assessed.
BP4
Available computational evidence is benign-leaning, but the BRCA1 BP4 rule is restricted to missense variants inside a clinically important functional domain with BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower.
BP5
No variant-specific clinical-history likelihood ratio meeting the BRCA1 ENIGMA BP5 thresholds was identified in the reviewed clinical-history materials, so BP5 was not assessed.
BP7
No reviewed RNA study showed a normal transcript profile for this variant, so BP7 was not assessed.
N/A · 10
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3
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 30765603
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
PMID 32546644
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
strong
Sources & reference links