About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.4189A>G, p.(Arg1397Gly)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
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
2 / 1,614,142 alleles
gnomAD v4.1: 2 / 1,614,142 alleles. Recorded AF 1.23905e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
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: 1 met · 6 not met · 8 not assessed · 11 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.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).
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.
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.
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.
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.
No criteria match.
Met · 1
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 exomes
- 2 alleles in gnomAD v4.1 (AF=1.24×10⁻⁶
- grpmax FAF=2.8×10⁻⁷)
- absent from gnomAD-Canada.
Still missing
- gnomAD v3.1 data not directly available
- v4.1 used as proxy.
Sources
Not met · 6 · evaluated, threshold not reached
PS1 No previously classified pathogenic missense variant at BRCA1 codon Arg1397 was identified in ENIGMA Table 9, Supplementary Tables, or ClinVar expert-reviewed submissions. PS1 requires a known pathogenic variant at the same amino acid position acting via the same mechanism. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator at Arg1397 found in ENIGMA functional assay tables or ClinVar.
Still missing
- Exhaustive ClinVar search for pathogenic missense at Arg1397 not performed beyond data provided.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
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. SpliceAI max delta is 0.04, well below the 0.2 threshold. No predicted pathogenic impact by ENIGMA bioinformatic criteria. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF=0.153 (threshold ≥0.28 not met)
- SpliceAI max delta=0.04 (threshold ≥0.2 not met)
- REVEL=0.594 (informational
- not an ENIGMA PP3 threshold).
Sources
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%). The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- grpmax FAF=2.8×10⁻⁷ << BA1 threshold 0.001.
Sources
BS1 The grpmax filter allele frequency is 2.8×10⁻⁷, below the ENIGMA BS1_Supporting threshold of FAF>0.00002 (0.002%). The variant is too rare to meet any BS1 strength level. Details ▾Hide ▴
Evidence considered
- grpmax FAF=2.8×10⁻⁷ < BS1_Supporting threshold 0.00002.
Sources
BP1 p.Arg1397Gly is located within the ENIGMA clinically important coiled-coil domain (aa 1391–1424). BP1_Strong requires the missense variant to be outside a clinically important functional domain and have no predicted splicing impact (SpliceAI≤0.1). The variant fails the domain location requirement. Details ▾Hide ▴
Evidence considered
- Variant is inside coiled-coil functional domain (aa 1391-1424)
- BP1 requires location outside functional domain.
Sources
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. Although SpliceAI max delta is 0.04 (≤0.1, no splicing predicted), the BayesDel threshold is not met. Both conditions must be satisfied for BP4 in a missense variant inside a functional domain. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF=0.153 > BP4 threshold 0.15
- SpliceAI max delta=0.04 ≤0.1 (passes splicing
- fails protein change prediction).
Sources
Not assessed · 8 · no assessment recorded
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). No variant-specific functional evidence from calibrated mammalian studies was identified. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA Table 9 and ST4 functional assay datasets.
Still missing
- No calibrated functional assay data available for this variant.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
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. Details ▾Hide ▴
Evidence considered
- No case-control data provided in case materials.
Still missing
- No case-control or cohort enrichment data available.
PP1 No cosegregation data or quantitative cosegregation likelihood ratio analysis was identified for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family cosegregation analysis data.
PP4 NM_007294.4:c.4189A>G (p.Arg1397Gly) is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No phenotype likelihood ratio can be computed. Also absent from the Parsons et al. 2019 (HUMU-40-1557-s001) multifactorial dataset. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 clinical-history LR table
- absent from Parsons et al. 2019 multifactorial LR dataset.
Still missing
- No clinical-history or multifactorial likelihood ratio data for this variant.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001
BS2 ENIGMA BS2 requires proband-level observation in the absence of Fanconi anemia phenotype features (Specifications Table 8). No proband-level data for this variant were available in the case materials. Details ▾Hide ▴
Evidence considered
- No proband-level phenotype data available.
Still missing
- No proband data to assess BS2 points.
BS3 NM_007294.4:c.4189A>G is not listed in ENIGMA Table 9 (curated functional assay results) or Supplementary Table 4. No calibrated functional evidence showing no damaging effect was identified for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ENIGMA functional assay datasets.
Still missing
- No calibrated functional assay data available.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BS4 No quantitative cosegregation analysis showing lack of segregation was identified for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family cosegregation data.
BP5 NM_007294.4:c.4189A>G is not listed in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table. No phenotype LR toward benignity can be computed. Details ▾Hide ▴
Evidence considered
- Variant absent from Li et al. 2020 clinical-history LR table.
Still missing
- No clinical-history LR data for benignity assessment.
Sources
vcep_pmid_31853058_brca1_clinical_history_lr
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.4189A>G is a missense variant (p.Arg1397Gly), not a null variant (nonsense, frameshift, canonical splice ±1,2). ENIGMA PVS1 applies only to null variants per Specifications Table 4. Details ▾Hide ▴
Evidence considered
- Missense substitution in BRCA1 exon 12
- not a null variant.
PS2 VCEPPS2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
PM1 VCEPPM1 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
PM5 N/AENIGMA PM5 is repurposed for protein termination codon (PTC) variants only. This is a missense variant (p.Arg1397Gly) and does not qualify. Classic same-residue missense PM5 is not used in the ENIGMA framework. Details ▾Hide ▴
Evidence considered
- Missense variant
- ENIGMA PM5 applies to PTC variants only.
Sources
pm5_candidates
PM6 VCEPPM6 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
PP2 VCEPPP2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
PP5 VCEPPP5 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
BP2 VCEPBP2 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
BP6 VCEPBP6 is marked Not Applicable by the ENIGMA BRCA1/2 cspec v1.2.0. Details ▾Hide ▴
BP7 N/ANM_007294.4:c.4189A>G is a missense variant inside the coiled-coil functional domain (aa 1391–1424). ENIGMA BP7_Supporting applies only to silent variants inside a functional domain or intronic variants at or beyond +7/−21, both contingent on BP4 being met (which it is not). BP7_Strong (RNA) requires BS3 for missense variants inside a functional domain, which is not available. Details ▾Hide ▴
Evidence considered
- Missense variant in functional domain
- BP7_Supporting for silent/intronic only
- BP7_Strong (RNA) requires BS3 which is not met.
Sources
PS5 N/APS5 is not included in the ENIGMA BRCA1/2 cspec v1.2.0 criteria set. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.4189A>G
- Protein (HGVS p.)
- NP_009225.1:p.(Arg1397Gly)
- GRCh38
- chr17:43082572 T>C
- GRCh37
- chr17:41234589 T>C
- ClinVar
- 3256349, 1741241, 1740750, 1740719, 1508878, 1424745, 37591
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
2 / 1,614,142 alleles
AF 1.24e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,142 alleles · 0 hom · FAF 2.8e-07
| European (non-Finnish)2 / 1,180,020 | 1.7e-06 |
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.
Statements
gnomAD 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.594
- BayesDel
- 0.153
How the predictions were used
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. SpliceAI max delta is 0.04, well below the 0.2 threshold. No predicted pathogenic impact by ENIGMA bioinformatic criteria. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF=0.153 (threshold ≥0.28 not met)
- SpliceAI max delta=0.04 (threshold ≥0.2 not met)
- REVEL=0.594 (informational
- not an ENIGMA PP3 threshold).
Sources
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. Although SpliceAI max delta is 0.04 (≤0.1, no splicing predicted), the BayesDel threshold is not met. Both conditions must be satisfied for BP4 in a missense variant inside a functional domain. Details ▾Hide ▴
Evidence considered
- BayesDel no-AF=0.153 > BP4 threshold 0.15
- SpliceAI max delta=0.04 ≤0.1 (passes splicing
- fails protein change prediction).
Sources
BP7 N/ANM_007294.4:c.4189A>G is a missense variant inside the coiled-coil functional domain (aa 1391–1424). ENIGMA BP7_Supporting applies only to silent variants inside a functional domain or intronic variants at or beyond +7/−21, both contingent on BP4 being met (which it is not). BP7_Strong (RNA) requires BS3 for missense variants inside a functional domain, which is not available. Details ▾Hide ▴
Evidence considered
- Missense variant in functional domain
- BP7_Supporting for silent/intronic only
- BP7_Strong (RNA) requires BS3 which is not met.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.594. BayesDel score = 0.15333.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 23918944 ↗Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.Observational cohort study examining whether adjuvant tamoxifen treatment for breast cancer is associated with reduced contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. No specific variant-level data are reported; the study analyzes clinical outcomes by carrier status, not individual variants.Does not name this variant
-
PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.American Society of Clinical Oncology · 2003American Society of Clinical Oncology 2003 policy statement on genetic testing for cancer susceptibility. General clinical practice guidance; does not discuss individual BRCA1 variants.Does not name this variant
-
PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors recommendations for cancer genetic risk assessment and counseling. General practice guidelines; does not discuss individual BRCA1 variants.Does not name this variant
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. Population-level screening recommendations; no individual variant data reported.Does not name this variant
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007National Society of Genetic Counselors practice recommendations for hereditary breast and ovarian cancer risk assessment and genetic counseling. Professional guidance document; does not report individual variant data.Does not name this variant
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008Review of the genetic basis of inherited breast cancer susceptibility, discussing broad classes of risk alleles. No individual variant-level data reported.Does not name this variant
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PMID 19305347 ↗ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.2009ACOG Practice Bulletin on hereditary breast and ovarian cancer syndrome. Clinical management guideline; no individual variant data.Does not name this variant
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010ASCO 2010 policy statement update on genetic and genomic testing for cancer susceptibility. Practice policy document; no individual variant data.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes the Sherloc refinement of ACMG-AMP variant classification criteria. Methodological framework paper; does not report functional data or observations for individual BRCA1 variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,614,142 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
2 Uncertain significance
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/variation/1508878/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41234589-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43082572-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43082572-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.4189…
- OncoKB ↗www.oncokb.org/gene/BRCA1/R1397G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.4189A%3EG
- 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= 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.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.