About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.670G>A, p.(Ala224Thr)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA1 VCEP v1.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP1Strong
BP1 · strong
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.
Recorded classification: 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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,612,828 alleles
gnomAD v4.1: 1 / 1,612,828 alleles. Recorded AF 6.20029e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 14 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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).
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.
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.
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.
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).
No criteria match.
Met · 2
PM2 SupportingPM2_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: 1/1
- 612
- 828 alleles (AF=6.2e-7
- 0 homozygotes)
- Highest subpopulation AF: European (non-Finnish) 1/1
- 179
- 100 (AF=8.5e-7)
Still missing
- gnomAD v3.1 data not directly queried
- v4.1 singleton suggests v3.1 would also show near-absence
Sources
BP1 StrongBP1_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. Details ▾Hide ▴
Evidence considered
- Missense variant p.Ala224Thr at position 224 — outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains
- SpliceAI max delta = 0.00 (≤0.1
- no splicing predicted)
- ENIGMA BP1_Strong rule: missense outside functional domains + no splicing predicted
Sources
Not met · 14 · evaluated, threshold not reached
PS1 No previously classified pathogenic missense variant at the same amino acid position (p.Ala224) was identified. The only same-codon comparator c.670G>C (p.Ala224Pro) is listed in ENIGMA Table 9 with no assigned PS3/BS3 code (PS3/BS3 not met) and has predicted splicing impact, whereas c.670G>A has no splicing impact (SpliceAI=0.0). No pathogenic comparator satisfies the PS1 rule requirements. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variant at residue Ala224 in ClinVar or ENIGMA resources
- c.670G>C (p.Ala224Pro) in Table9 has no assigned code and predicted splicing
- not a valid PS1 comparator
- SpliceAI=0.0 for c.670G>A differs from predicted splicing for c.670G>C
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18
PS3 No well-established functional assay data demonstrating a damaging effect on BRCA1 protein function was identified for c.670G>A. ENIGMA Specifications Table 9 (calibrated functional studies) does not list this variant. ST4 functional assay dataset does not contain c.670G>A. No variant-specific functional evidence was found in the literature. Details ▾Hide ▴
Evidence considered
- ENIGMA Table9 does not include c.670G>A (includes c.670G>C but not c.670G>A)
- ST4 functional assay dataset contains no entry for c.670G>A
- No published functional study testing p.Ala224Thr identified
Still missing
- No calibrated functional assay has tested the impact of p.Ala224Thr on BRCA1 function
Sources
PS4 No case-control data demonstrating significantly increased prevalence of c.670G>A in affected individuals versus controls was identified. The variant is absent from ClinVar and no published studies report variant counts in breast/ovarian cancer cohorts. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 shows 1 allele in 1
- 612
- 828 (AF=6.2e-7) — extremely rare in general population
- No case-control studies or cohort enrichment data available
- Absent from ClinVar submissions
Still missing
- No case series or consortium data (e.g.
- CIMBA
- ENIGMA) reporting carrier counts in affected individuals
Sources
PP1 No co-segregation data was identified for c.670G>A. No family studies or pedigrees demonstrating segregation of this variant with breast/ovarian cancer in affected family members were found in public databases (ClinVar, LOVD, BRCA Exchange) or the literature. Details ▾Hide ▴
Evidence considered
- No co-segregation analysis published for this variant
- Exploratory search found no family-based studies with c.670G>A
Still missing
- No multi-generation segregation data available
- ENIGMA consortium may hold unpublished family data
Sources
PP3 PP3 is not met under ENIGMA rules. The variant (p.Ala224Thr, position 224) lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel no-AF score (0.183) is below the ≥0.28 threshold. SpliceAI max delta (0.00) is below the ≥0.2 threshold. No predicted impact via protein change or splicing. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score: 0.183 (<0.28 PP3 threshold
- >0.15 BP4 threshold — intermediate zone)
- SpliceAI max delta: 0.00 (no splicing predicted)
- REVEL score: 0.541 (not used independently by ENIGMA for PP3)
- Position 224 outside all three functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857)
Sources
PP4 PP4 is not met. The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.76 (based on 1 proband), which falls in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 can be applied. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 BRCA1 clinical-history LR: 1.76 (1 proband)
- LR falls in neutral zone (>0.48 and <2.08) — neither pathogenic nor benign direction met
- PP4 Supporting requires LR ≥2.08
Sources
BA1 BA1 is not met. The variant frequency in gnomAD is well below the ENIGMA BA1 threshold (FAF > 0.1%). gnomAD v2.1: absent. gnomAD v4.1: AF=6.2e-7 (0.000062%). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=6.2e-7 (far below 0.1% BA1 threshold)
Sources
BS1 BS1 is not met. The variant frequency is below both the BS1_Strong threshold (FAF > 0.01%) and the BS1_Supporting threshold (FAF > 0.002%). gnomAD v2.1: absent. gnomAD v4.1: AF=6.2e-7 (0.000062%), below the 0.002% (2e-5) BS1_Supporting threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=6.2e-7 — below BS1_Supporting threshold of 0.002% (FAF > 0.00002)
Sources
BS2 BS2 requires observation of the variant in trans with a pathogenic variant in healthy individuals (absence of Fanconi anemia phenotype). No such data is available for c.670G>A. Details ▾Hide ▴
Evidence considered
- No co-occurrence data in healthy individuals identified
- No Fanconi anemia case reports involving c.670G>A
Still missing
- No data on co-occurrence in trans with known pathogenic BRCA1 variants in healthy individuals
BS3 No well-established functional assay data demonstrating no damaging effect on BRCA1 protein function was identified for c.670G>A. ENIGMA Specifications Table 9 does not list this variant for BS3. ST4 functional assay dataset contains no entry for c.670G>A. Details ▾Hide ▴
Evidence considered
- ENIGMA Table9 does not include c.670G>A for BS3
- ST4 functional assay dataset: no entry for c.670G>A
- No calibrated study reports neutral effect for p.Ala224Thr
Still missing
- No functional assay has tested p.Ala224Thr for neutral/benign effect on BRCA1 function
Sources
BS4 No lack of segregation data was identified for c.670G>A. No study reports affected family members who do not carry this variant. Details ▾Hide ▴
Evidence considered
- No non-segregation observations in affected families identified
Still missing
- No pedigree data available to assess lack of segregation
BP4 BP4 is not met. The primary BP4 rule requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 and SpliceAI ≤0.1. Position 224 is outside all three functional domains. Additionally, BayesDel no-AF score (0.183) exceeds the ≤0.15 threshold. The intronic BP4 rule does not apply as this is an exonic variant. Details ▾Hide ▴
Evidence considered
- Position 224 outside functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857)
- BayesDel no-AF: 0.183 (>0.15 BP4 threshold)
- SpliceAI max delta: 0.00 (≤0.1)
Sources
BP5 BP5 is not met. The variant-specific clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is LR=1.76 (1 proband), which falls in the neutral zone (>0.48 and <2.08). BP5 Supporting requires LR ≤0.48. Details ▾Hide ▴
Evidence considered
- Li et al. 2020 BRCA1 clinical-history LR: 1.76 (1 proband)
- LR falls in neutral zone — BP5 not applicable (requires LR ≤0.48)
Sources
BP7 BP7 is not met. BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile — no such data exists for c.670G>A. BP7_Supporting applies only to silent variants inside functional domains (if BP4 met) or intronic variants at positions ≥+7/-21 (if BP4 met). This variant is a missense outside functional domains and is exonic. Details ▾Hide ▴
Evidence considered
- No mRNA splicing assay data for c.670G>A — BP7_Strong (RNA) not applicable
- Variant is missense
- not silent — BP7_Supporting rule for silent variants not applicable
- Variant is exonic — BP7_Supporting rule for intronic variants not applicable
Still missing
- No mRNA transcript analysis has been performed for c.670G>A
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants under the ENIGMA BRCA1 VCEP. NM_007294.4:c.670G>A is a missense substitution (p.Ala224Thr), not a null variant (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon deletion). SpliceAI predicts no splicing impact (max delta = 0.0). Details ▾Hide ▴
Evidence considered
- Missense variant class
- not a null variant
- SpliceAI max delta score 0.00 confirms no splice-altering effect
- pvs1_variant_assessment assigns variant_bucket='other' and apply_generic_pvs1_framework=false
Sources
PS2 VCEPPS2 (de novo) is not part of the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0 criteria set. PM6 (also de novo) is explicitly marked Not Applicable by the CSPEC framework. Details ▾Hide ▴
Evidence considered
- PS2 not listed in ENIGMA BRCA1 VCEP criteria
- PM6 explicitly marked Not Applicable
Sources
PM1 VCEPPM1 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
PM5 N/APM5 in the ENIGMA BRCA1 VCEP is repurposed exclusively for protein termination codon (PTC) variants in exons where a proven pathogenic PTC has been observed (PM5_PTC). c.670G>A is a missense variant, not a PTC. Details ▾Hide ▴
Evidence considered
- ENIGMA PM5 rule applies only to PTC variants
- pm5_candidates.json: pm5_mode='ptc_gene_specific'
- eligible_for_classic_pm5_search=false
- Missense variant p.Ala224Thr is not a protein termination codon
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
PP2 VCEPPP2 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
PP5 VCEPPP5 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
BP2 VCEPBP2 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
BP6 VCEPBP6 is explicitly marked Not Applicable in the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0. Details ▾Hide ▴
PS5 N/APS5 is not part of the ENIGMA BRCA1 and BRCA2 VCEP specification v1.2.0 criteria set. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.670G>A
- Protein (HGVS p.)
- NP_009225.1:p.(Ala224Thr)
- GRCh38
- chr17:43095846 C>T
- GRCh37
- chr17:41247863 C>T
Gene diagram
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,612,828 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,612,828 alleles · 0 hom
| European (non-Finnish)1 / 1,179,100 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.541
- BayesDel
- 0.183
How the predictions were used
PP3 PP3 is not met under ENIGMA rules. The variant (p.Ala224Thr, position 224) lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). BayesDel no-AF score (0.183) is below the ≥0.28 threshold. SpliceAI max delta (0.00) is below the ≥0.2 threshold. No predicted impact via protein change or splicing. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF score: 0.183 (<0.28 PP3 threshold
- >0.15 BP4 threshold — intermediate zone)
- SpliceAI max delta: 0.00 (no splicing predicted)
- REVEL score: 0.541 (not used independently by ENIGMA for PP3)
- Position 224 outside all three functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857)
Sources
BP4 BP4 is not met. The primary BP4 rule requires the variant to be inside a clinically important functional domain with BayesDel ≤0.15 and SpliceAI ≤0.1. Position 224 is outside all three functional domains. Additionally, BayesDel no-AF score (0.183) exceeds the ≤0.15 threshold. The intronic BP4 rule does not apply as this is an exonic variant. Details ▾Hide ▴
Evidence considered
- Position 224 outside functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857)
- BayesDel no-AF: 0.183 (>0.15 BP4 threshold)
- SpliceAI max delta: 0.00 (≤0.1)
Sources
BP7 BP7 is not met. BP7_Strong (RNA) requires well-established functional studies showing no damaging effect on mRNA transcript profile — no such data exists for c.670G>A. BP7_Supporting applies only to silent variants inside functional domains (if BP4 met) or intronic variants at positions ≥+7/-21 (if BP4 met). This variant is a missense outside functional domains and is exonic. Details ▾Hide ▴
Evidence considered
- No mRNA splicing assay data for c.670G>A — BP7_Strong (RNA) not applicable
- Variant is missense
- not silent — BP7_Supporting rule for silent variants not applicable
- Variant is exonic — BP7_Supporting rule for intronic variants not applicable
Still missing
- No mRNA transcript analysis has been performed for c.670G>A
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.541. BayesDel score = 0.183223.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,612,828 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1530970787
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_007294.4%3Ac.670G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41247863-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43095846-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.670G…
- OncoKB ↗www.oncokb.org/gene/BRCA1/A224T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.670G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant is absent from ClinVar.
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 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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.