NM_007294.4:c.4189A>G (p.Arg1397Gly) is a rare missense variant in BRCA1 exon 12, located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424).1 The variant is absent from gnomAD v2.1 and observed at extremely low frequency in gnomAD v4.1 (2/1,614,142 alleles; grpmax FAF=2.8×10⁻⁷), meeting ENIGMA PM2_Supporting.2 In silico predictions are indeterminate: REVEL score is 0.594 (elevated), but the ENIGMA-specified BayesDel no-AF score of 0.153 falls between the BP4 threshold (≤0.15) and PP3 threshold (≥0.28), and SpliceAI predicts no splicing impact (max delta=0.04). Neither PP3 nor BP4 is met.3 No variant-specific functional data, clinical-history likelihood ratios, cosegregation analysis, or case-control data were identified in the ENIGMA VCEP materials or literature reviewed.4 With only PM2_Supporting met and no other applicable criteria, the evidence is insufficient to classify this variant beyond Uncertain Significance (VUS) under the ENIGMA BRCA1/2 v1.2.0 framework. The combination of a single supporting-level pathogenic criterion does not reach the Likely Pathogenic threshold.5
BRCA1
Final classification
VUS
BRCA1 c.4189A>G · p.Arg1397Gly
BRCA1
NM_007294.4:c.4189A>G (p.Arg1397Gly) is a rare missense variant in BRCA1 exon 12, located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424).
Only one pathogenic criterion (PM2_Supporting) is met. Under ENIGMA BRCA1/2 v1.2.0 Table 3 combination rules, a single Supporting-level criterion does not satisfy any Likely Pathogenic or Pathogenic combination threshold. No benign criteria are met. The evidence is insufficient to classify beyond Uncertain Significance.
Classification rationale
PM2
VUS
BRCA1 c.4189A>G
PM2
→
VUS
1
cspec ↗
3
bayesdelrevelspliceai ↗cspec ↗
4
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_pmid_31853058_brca1_clinical_history_lr
5
cspec ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 14 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_007294.4:c.4189A>G is absent from gnomAD v2.1 (non-cancer, exome). In gnomAD v4.1, it is observed at extremely low frequency (2/1,614,142 alleles; grpmax FAF=2.8×10⁻⁷), effectively absent from outbred control populations. Meets ENIGMA PM2_Supporting threshold.
Absent from gnomAD v2.1 exomes2 alleles in gnomAD v4.1 (AF=1.24×10⁻⁶grpmax FAF=2.8×10⁻⁷)
Assessed · not applied
Pathogenic
PS1
No previously classified pathogenic missense variant at BRCA1 codon Arg1397 was identified in ENIGMA Table 9, Supplementary Tables, or ClinVar expert-reviewed submissions.
PS3
NM_007294.4:c.4189A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4 (full functional assay dataset).
PS4
No case-control study data with p-value and odds ratio meeting ENIGMA PS4 thresholds (p≤0.05, OR≥4, lower CI excludes 2.0) was identified for this variant.
PP1
No cosegregation data or quantitative cosegregation likelihood ratio analysis was identified for this variant.
PP3
p.Arg1397Gly lies within the ENIGMA clinically important coiled-coil domain (aa 1391–1424), but BayesDel no-AF score is 0.153, below the ENIGMA PP3 threshold of ≥0.28.
PP4
NM_007294.4:c.4189A>G (p.Arg1397Gly) is not listed in the Li et al.
Benign
BA1
The grpmax filter allele frequency in gnomAD v4.1 is 2.8×10⁻⁷, far below the ENIGMA BA1 threshold of FAF>0.001 (0.1%).
BS1
The grpmax filter allele frequency is 2.8×10⁻⁷, below the ENIGMA BS1_Supporting threshold of FAF>0.00002 (0.002%).
BS2
ENIGMA BS2 requires proband-level observation in the absence of Fanconi anemia phenotype features (Specifications Table 8).
BS3
NM_007294.4:c.4189A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4.
BS4
No quantitative cosegregation analysis showing lack of segregation was identified for this variant.
BP1
p.Arg1397Gly is located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424).
BP4
p.Arg1397Gly lies within the coiled-coil functional domain, but BayesDel no-AF score is 0.153, exceeding the ENIGMA BP4 threshold of ≤0.15.
BP5
NM_007294.4:c.4189A>G is not listed in the Li et al.
N/A · 10
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23905e-06; MAF= 0.00012%, 2/1614142 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69489e-06; MAF= 0.00017%, 2/1180020 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,614,142
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,180,020 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1508878)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.594. BayesDel score = 0.15333.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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.
Sources & reference links
9Sources
Triaged references · 9 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
20065170 ↗
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR