PS3_Strong is met: three independent calibrated functional studies (Findlay 2018, Petitalot 2019, Fernandes 2019) demonstrate that p.Gln1811Arg exhibits protein function comparable to pathogenic control variants (ENIGMA Table 9; functional impact complete, IARC class 5).1 PM2_Supporting is met: the variant is absent from gnomAD v2.1 (non-cancer exomes) and observed at extremely low frequency in gnomAD v4.1 (1/1,614,234 alleles; AF=6.19×10⁻⁷).2 PP3 and BP4 are not met: BayesDel no-AF score of 0.192 falls in the intermediate range between the BP4 threshold (≤0.15) and the PP3 threshold (≥0.28) for variants inside the BRCT clinically important domain.3 PP4 and BP5 are not met: the clinical-history likelihood ratio (LR=0.993 from Li et al. 2020, N=3 probands) falls within the neutral zone, neither supporting pathogenicity nor benignity.4 PVS1, PM5, and BP1 are not applicable: PVS1 is restricted to null variants; PM5_PTC is N/A for exon E21(22) per ENIGMA Table 4; BP1 requires location outside a clinically important functional domain (Gln1811 is within the BRCT domain).5 Under ENIGMA Table 3 combining rules, the evidence profile of one Strong criterion (PS3) plus one Supporting criterion (PM2) is insufficient to classify as Likely Pathogenic (requires ≥2 Strong, or 1 Strong + ≥2 Supporting, or 1 Strong + 1–2 Moderate). The variant is classified as a Variant of Uncertain Significance (VUS).6
BRCA1
Final classification
VUS
PS3PM2
BRCA1
c.5432A>G
p.Gln1811Arg
This variant
PS3_Strong is met: three independent calibrated functional studies (Findlay 2018, Petitalot 2019, Fernandes 2019) demonstrate that p.Gln1811Arg exhibits protein function comparable to pathogenic control variants (ENIGMA Table 9; functional impact complete, IARC class 5).
ENIGMA BRCA1 Table 3 combining rules applied: one Strong criterion (PS3) plus one Supporting criterion (PM2) does not satisfy any Likely Pathogenic combination (requires 2 Strong, or 1 Strong + 2 Supporting, or 1 Strong + 1-2 Moderate). No benign criteria are met. Under the ENIGMA point-based scoring system, PS3_Strong (4 pts) + PM2_Supporting (1 pt) = 5 pts, which falls within the Uncertain Significance range (-1 to 5). The variant is classified as a Variant of Uncertain Significance (VUS).
Classification rationale
PS3PM2
VUS
BRCA1 c.5432A>G
PS3 + PM2
→
VUS
1
vcep_specifications_table9_v1_2_2024_11_18
3
bayesdelcspec ↗
4
vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
5
cspec ↗vcep_specifications_table4_v1_2_2024_11_18
6
cspec ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
strong
Pathogenic
ENIGMA BRCA1 VCEP Table 9 assigns PS3_Strong for NM_007294.3:c.5432A>G (p.Gln1811Arg) based on three calibrated functional studies (Findlay 2018 PMID:30209399; Petitalot 2019 PMID:30257991; Fernandes 2019 PMID:30765603), all reporting protein function similar to pathogenic control variants. In the ENIGMA Supplementary Table 4 (ST4) functional assay dataset, this variant shows complete functional impact (LOF, IARC class 5 — Pathogenic) with three independent supporting publications.
ENIGMA Table 9: PS3_Strong assigned — three calibrated studies show protein function similar to pathogenic controls.ENIGMA ST4: Functional impact — complete (LOF)IARC class 5 (Pathogenic)
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (non-cancer, exome only subset). In gnomAD v4.1, one allele is observed in 1,614,234 alleles (AF=6.19×10⁻⁷; 0.00006%), in the European (non-Finnish) population. This extremely low population frequency meets the ENIGMA PM2_Supporting threshold (absent from v2.1 and v3.1 non-cancer subsets). The single allele in v4.1 at near-zero frequency does not negate this criterion.
Absent from gnomAD v2.1 (non-cancerexome).gnomAD v4.1: 1/1
Assessed · not applied
· 10 not met · 4 not assessed
Pathogenic
PS1
No same-amino-acid-change comparator variant at position Gln1811 has been independently classified as Pathogenic or Likely Pathogenic by the ENIGMA expert panel.
PS4
No case-control study with odds ratio and p-value meeting ENIGMA PS4 thresholds (p≤0.05, OR≥4, lower CI excludes 2.0) has been identified for this variant.
PP1
No co-segregation data or quantitative Bayes score analysis has been identified for this variant.
PP3
The variant lies within the BRCT clinically important functional domain (aa 1650–1857; Gln1811).
PP4
The clinical-history likelihood ratio from Li et al.
Benign
BA1
ENIGMA BA1 threshold requires a filter allele frequency (FAF) >0.001 (0.1%) in gnomAD v2.1 and/or v3.1 non-cancer, non-founder populations.
BS1
ENIGMA BS1_Strong requires FAF >0.0001 (0.01%); BS1_Supporting requires FAF >0.00002 (0.002%) and ≤0.0001 (0.01%).
BS2
No data on observation of this variant in healthy adult individuals without features of Fanconi anemia were available for ENIGMA BS2 point-based assessment.
BS3
ENIGMA Table 9 assigns PS3_Strong for this variant based on calibrated functional studies showing protein function similar to pathogenic controls.
BS4
No lack-of-segregation data or quantitative Bayes score analysis has been identified for this variant.
BP1
ENIGMA BP1_Strong applies to missense variants located outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1).
BP4
The variant lies within the BRCT clinically important functional domain.
BP5
The clinical-history likelihood ratio from Li et al.
BP7
ENIGMA BP7_Strong (RNA) applies to missense variants located outside a clinically important functional domain with mRNA evidence of no splicing impact.
N/A · 9
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19489e-07; MAF= 0.00006%, 1/1614234 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47426e-07; MAF= 0.00008%, 1/1180044 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,614,234
0 hom
0 hom
European (non-Finnish) 1 / 1,180,044 |
8.5e-05% |
+ 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 Likely pathogenic (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Likely Pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 55578)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.709. BayesDel score = 0.192033.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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 · 7 PMIDs not cited in assessment
15172985 ↗
Structure-based assessment of missense mutations in human BRCA1: implications for breast and ovarian cancer predisposition.
ONCOKB
20516115 ↗
Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays.
ONCOKB
12496477 ↗
Mutations in the BRCT domain confer temperature sensitivity to BRCA1 in transcription activation.
CLINVAR
14534301 ↗
Detection of protein folding defects caused by BRCA1-BRCT truncation and missense mutations.
CLINVAR
15235020 ↗
Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.
CLINVAR