NM_007294.4:c.2347A>G (p.Ile783Val) is observed in gnomAD at a filter allele frequency of 0.0632% (18/250,738 alleles in v2.1, grpmax FAF in East Asian population), exceeding the ENIGMA BS1_Strong threshold of 0.01%.1 A calibrated functional study (Bouwman et al. 2020, PMID:32546644) demonstrated that p.Ile783Val exhibits protein function similar to benign control variants in a homologous recombination repair complementation assay. ENIGMA Specifications Table 9 assigns BS3_Strong to this variant.2 The variant is a missense substitution at amino acid 783, located outside all ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), with no predicted splicing impact (SpliceAI max delta=0.0), satisfying ENIGMA BP1_Strong.3 Three strong benign criteria (BS1, BS3, BP1) are met, satisfying ENIGMA Table 3 rule for Benign classification (≥2 Strong Benign criteria).4
BRCA1
Final classification
Benign
BRCA1 c.2347A>G · p.Ile783Val
BRCA1
NM_007294.4:c.2347A>G (p.Ile783Val) is observed in gnomAD at a filter allele frequency of 0.0632% (18/250,738 alleles in v2.1, grpmax FAF in East Asian population), exceeding the ENIGMA BS1_Strong threshold of 0.01%.
ENIGMA BRCA1 v1.2 Table 3 combination rules. Three strong benign criteria met (BS1_Strong, BS3_Strong, BP1_Strong), satisfying the rule: ≥2 Strong (Benign) criteria → Benign. No pathogenic criteria are met, so the ENIGMA conflicting-evidence point system is not invoked.
Classification rationale
BS1BS3BP1
Benign
BRCA1 c.2347A>G
BS1 + BS3 + BP1
→
Benign
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 13 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
ENIGMA BS1_Strong: filter allele frequency (FAF) >0.01% (0.0001) in gnomAD non-cancer, non-founder populations. This variant has grpmax FAF = 0.0632% (0.000632) in gnomAD v2.1 East Asian population (18/18,394 alleles, AF=0.098%) and grpmax FAF = 0.0223% (0.000223) in gnomAD v4.1. Both exceed the BS1_Strong threshold. The East Asian population is not a founder population under ENIGMA criteria.
gnomAD v2.1 grpmax FAF=0.0632% > 0.01% threshold (East Asian subpopulation)gnomAD v4.1 grpmax FAF=0.0223% > 0.01% thresholdVariant observed at highest frequency in East Asian population (v2.1 AF=0.098%
✓
BS3
strong
Benign
ENIGMA Specifications Table 9 assigns BS3_Strong to NM_007294.4:c.2347A>G (p.Ile783Val). A calibrated functional study (Bouwman 2020, PMID:32546644) demonstrated that this variant exhibits protein function similar to benign control variants in a homologous recombination repair complementation assay, indicating no damaging effect on protein function.
ENIGMA Table 9 assigns BS3_Strong based on Bouwman 2020 (PMID:32546644)Homologous recombination repair complementation assay showed (likely) neutral functional effect
✓
BP1
strong
Benign
ENIGMA BP1_Strong applies to missense variants located outside a (potentially) clinically important functional domain AND with no predicted splicing impact (SpliceAI ≤0.1). p.Ile783Val is a missense variant at amino acid position 783, which is outside all three ENIGMA-defined clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta score is 0.0, confirming no predicted splicing impact.
Missense variant at position 783 — outside RING (2-101)coiled-coil (1391-1424)and BRCT (1650-1857) domains
Assessed · not applied
Pathogenic
PS1
No previously classified pathogenic or likely pathogenic missense variant at the same residue (Ile783) was identified in available data.
PS3
ENIGMA Specifications Table 9 assigns BS3_Strong to c.2347A>G (p.Ile783Val), indicating calibrated functional studies demonstrate protein function similar to benign control variants (Bouwman 2020, PMID:32546644).
PS4
No case-control data available for this variant.
PM2
ENIGMA PM2_Supporting requires absence from controls in gnomAD v2.1 (non-cancer, exome) and gnomAD v3.1 (non-cancer).
PP1
No co-segregation data available for this variant.
PP3
ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel ≥0.28, or when SpliceAI ≥0.2.
PP4
Variant c.2347A>G was not found in the ENIGMA clinical history likelihood ratio table (Li et al.
Benign
BA1
ENIGMA BA1 requires filter allele frequency (FAF) >0.1% (0.001) in gnomAD v2.1 non-cancer exome and/or gnomAD v3.1 non-cancer, non-founder populations.
BS2
ENIGMA BS2 requires proband-level data evaluated per Specifications Table 8, applied in the absence of Fanconi Anemia phenotype features.
BS4
ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation (LR thresholds).
BP4
ENIGMA BP4 applies to missense variants inside a clinically important functional domain with no predicted impact via protein change or splicing (BayesDel ≤0.15 AND SpliceAI ≤0.1).
BP5
Variant c.2347A>G was not found in the ENIGMA clinical history likelihood ratio table (Li et al.
BP7
ENIGMA BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile (mRNA assay only).
N/A · 12
PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.11535e-05; MAF= 0.00112%, 18/1613836 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000356459; MAF= 0.03565%, 16/44886 alleles, homozygotes = 0); grpmax FAF= 0.00022308.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.17881e-05; MAF= 0.00718%, 18/250738 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00097858; MAF= 0.09786%, 18/18394 alleles, homozygotes = 0); grpmax FAF= 0.00063201.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0011%
· 18 / 1,613,836
0 hom · FAF 0.022%
0 hom · FAF 0.022%
East Asian 16 / 44,886 |
0.036% |
Remaining individuals 2 / 62,478 |
0.0032% |
+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0072%
· 18 / 250,738
0 hom · FAF 0.063%
0 hom · FAF 0.063%
East Asian 18 / 18,394 |
0.098% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 54541)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.24. BayesDel score = -0.316337.
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
15385441 ↗
Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.
CLINVAR
16267036 ↗
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
30702160 ↗
Germline variation in BRCA1/2 is highly ethnic-specific: Evidence from over 30,000 Chinese hereditary breast and ovarian cancer patients.
CLINVAR
31911673 ↗
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
CLINVAR
34326862 ↗
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR