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BRCA1
Final classification
Likely Benign
BRCA1 c.670G>A · p.Ala224Thr
BRCA1

NM_007294.4:c.670G>A (p.Ala224Thr) is a missense variant in BRCA1 exon 9(10).

Gene
BRCA1
Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.670G>A
Consequence
N/A
GRCh38
chr17:43095846 C>T
GRCh37
chr17:41247863 C>T
Basis ENIGMA Table 3 point system for conflicting evidence: BP1_Strong (-4 benign points) + PM2_Supporting (+1 pathogenic point) = -3 total. Range -6 to -2 = Likely Benign.
ENIGMA Table 3 point system for conflicting evidence: BP1_Strong (-4 benign points) + PM2_Supporting (+1 pathogenic point) = -3 total. Range -6 to -2 = Likely Benign.
Classification rationale
PM2 BP1 Likely Benign
BRCA1 c.670G>A

NM_007294.4:c.670G>A (p.Ala224Thr) is a missense variant in BRCA1 exon 9(10). This variant is absent from gnomAD v2.1 and present as a singleton in gnomAD v4.1 (1/1,612,828 alleles, AF=6.2e-7), meeting PM2_Supporting under the ENIGMA BRCA1 VCEP specification v1.2.0.1 BP1_Strong is applied: the variant is a missense substitution located at amino acid position 224, which lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI predicts no splicing impact (max delta = 0.00).2 BayesDel no-AF score is 0.183, falling in the intermediate zone between BP4 (≤0.15) and PP3 (≥0.28); REVEL score is 0.541. Neither PP3 nor BP4 can be applied.3 The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 1.76 based on 1 proband, falling in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 is applicable.4 No functional assay data (PS3/BS3), case-control data (PS4), co-segregation data (PP1/BS4), or same-residue pathogenic comparator (PS1) was identified for this variant.5 Under the ENIGMA Table 3 combining rules, the evidence consists of BP1_Strong (1 strong benign) and PM2_Supporting (1 supporting pathogenic). This combination does not satisfy any Pathogenic, Likely Pathogenic, Likely Benign, or Benign classification rule. The variant is classified as a Variant of Uncertain Significance (VUS).6

PM2 + BP1 Likely Benign
3 bayesdelrevelcspec ↗
4 PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lr
5 vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
6 cspec ↗final_classification_framework
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
PM2_Supporting is met under ENIGMA rules. The variant is absent from gnomAD v2.1 (non-cancer, exome only subset) and present as a singleton in gnomAD v4.1 (1/1,612,828 alleles, AF=6.2e-7), consistent with absence from controls in an outbred population. The region around the variant has adequate read depth.
gnomAD v2.1: absentgnomAD v4.1: 1/1612
BP1 strong Benign
BP1_Strong is met under ENIGMA rules. c.670G>A is a missense variant (p.Ala224Thr) located at amino acid position 224, which is outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI predicts no splicing impact (max delta = 0.00, ≤0.1). All conditions for BP1_Strong are satisfied.
Missense variant p.Ala224Thr at position 224 — outside RING (2-101)coiled-coil (1391-1424)and BRCT (1650-1857) domains
Assessed · not applied
Pathogenic
PS1 No previously classified pathogenic missense variant at the same amino acid position (p.Ala224) was identified.
PS3 No well-established functional assay data demonstrating a damaging effect on BRCA1 protein function was identified for c.670G>A.
PS4 No case-control data demonstrating significantly increased prevalence of c.670G>A in affected individuals versus controls was identified.
PP1 No co-segregation data was identified for c.670G>A.
PP3 PP3 is not met under ENIGMA rules.
PP4 PP4 is not met.
Benign
BA1 BA1 is not met.
BS1 BS1 is not met.
BS2 BS2 requires observation of the variant in trans with a pathogenic variant in healthy individuals (absence of Fanconi anemia phenotype).
BS3 No well-established functional assay data demonstrating no damaging effect on BRCA1 protein function was identified for c.670G>A.
BS4 No lack of segregation data was identified for c.670G>A.
BP4 BP4 is not met.
BP5 BP5 is not met.
BP7 BP7 is not met.
N/A · 9 PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP5 · BP2 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.20029e-07; MAF= 0.00006%, 1/1612828 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48104e-07; MAF= 0.00008%, 1/1179100 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05% · 1 / 1,612,828
0 hom
European (non-Finnish)
1 / 1,179,100
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
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.541. BayesDel score = 0.183223.
Functional / OncoKB screenshot
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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
8Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
SpliceAI
OncoKB
COSMIC
Cancer hotspots