About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.4935G>C, p.(Arg1645Ser)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A 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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 (exome, non-cancer) and gnomAD v4.1 (non-cancer). Per ENIGMA v1.2, PM2_Supporting applies when a variant is absent from controls in outbred populations (read depth >=25 assumed per pipeline).
Benign criteria applied · 2
BS3Strong
BS3 · strong
ENIGMA Table 9 assigns BS3 (Strong) to c.4935G>C (p.Arg1645Ser). Two calibrated functional studies demonstrate protein function similar to benign control variants: Findlay et al. 2018 (PMID:30209399, saturation genome editing, classification: FUNC) and Fernandes et al. 2019 (PMID:30765603, BRCT domain functional assay, classification: Not Pathogenic). ST4 confirms no functional impact with FUNC classification.
BP1Strong
BP1 · strong
ENIGMA BP1_Strong applies to missense variants located outside a clinically important functional domain with no splicing predicted. Arg1645 (position 1645) lies outside all three BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta is 0.02 (<=0.1), predicting no splicing impact.
Recorded classification: Benign
ENIGMA BRCA1/BRCA2 v1.2 Table 3 conflicting-evidence point system: BS3 Strong (-4) + BP1 Strong (-4) + PM2 Supporting (+1) = -7, which meets the Benign threshold (<= -7). The two Strong benign criteria also independently satisfy the ENIGMA Table 3 benign combination rule (2 Strong Benign -> 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
9 reported laboratory submissions
6 Uncertain significance · 3 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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.
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: 3 met · 8 not met · 6 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
c.4935G>C (p.Arg1645Ser) is a missense variant in BRCA1 exon 15, located at amino acid position 1645, five residues N-terminal to the BRCT domain (aa 1650-1857).
ENIGMA BRCA1 VCEP Table 9 assigns BS3 (Strong) to this variant based on two calibrated functional studies demonstrating protein function indistinguishable from benign control variants (Findlay 2018, PMID:30209399; Fernandes 2019, PMID:30765603).
ENIGMA BP1_Strong applies because the variant is a missense substitution located outside all 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 0.02).
PM2_Supporting is met because the variant is absent from gnomAD v2.1 and v4.1 in outbred populations.
Per ENIGMA Table 3 combining rules, two Strong Benign criteria (BS3 + BP1) meet the threshold for Benign classification. The single Supporting Pathogenic criterion (PM2) does not alter the classification.
Final classification: Benign.
No criteria match.
Met · 3
PM2 SupportingVariant is absent from gnomAD v2.1 (exome, non-cancer) and gnomAD v4.1 (non-cancer). Per ENIGMA v1.2, PM2_Supporting applies when a variant is absent from controls in outbred populations (read depth >=25 assumed per pipeline). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Still missing
- Read depth confirmation at variant position not explicitly verified
Sources
BS3 StrongENIGMA Table 9 assigns BS3 (Strong) to c.4935G>C (p.Arg1645Ser). Two calibrated functional studies demonstrate protein function similar to benign control variants: Findlay et al. 2018 (PMID:30209399, saturation genome editing, classification: FUNC) and Fernandes et al. 2019 (PMID:30765603, BRCT domain functional assay, classification: Not Pathogenic). ST4 confirms no functional impact with FUNC classification. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: c.4935G>C BS3 Strong
- Findlay 2018: saturation genome editing
- FUNC (no functional impact)
- Fernandes 2019: BRCT domain assay
- Not Pathogenic
- ST4: No functional impact
- FUNC
- not depleted
Sources
BP1 StrongENIGMA BP1_Strong applies to missense variants located outside a clinically important functional domain with no splicing predicted. Arg1645 (position 1645) lies outside all three BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). SpliceAI max delta is 0.02 (<=0.1), predicting no splicing impact. Details ▾Hide ▴
Evidence considered
- Position 1645 is outside all BRCA1 functional domains (RING 2-101
- coiled-coil 1391-1424
- BRCT 1650-1857)
- SpliceAI max delta: 0.02 (<=0.1 threshold)
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No pathogenic missense variant has been established at residue Arg1645. All other missense substitutions at this residue (R1645G, R1645K, R1645T) are assigned BS3 (benign functional evidence) by ENIGMA Table 9, precluding a pathogenic comparator for PS1. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: c.4933A>G (R1645G) BS3 Strong
- c.4934G>A (R1645K) BS3 Strong
- c.4934G>C (R1645T) BS3 Strong
Sources
vcep_specifications_table9_v1_2_2024_11_18
PS3 ENIGMA Table 9 assigns BS3 (Strong) to c.4935G>C based on two calibrated functional studies (Findlay 2018 PMID:30209399, Fernandes 2019 PMID:30765603) showing protein function similar to benign control variants. ST4 functional assay also reports 'No functional impact' with FUNC classification. No evidence of damaging effect exists for this variant. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: c.4935G>C assigned BS3 Strong
- ST4: No functional impact
- FUNC classification
- Findlay 2018: saturation genome editing
- FUNC
- Fernandes 2019: BRCT domain assay
- Not Pathogenic
Sources
PP3 PP3 for missense variants requires location inside a clinically important functional domain AND BayesDel no-AF score >=0.28. Arg1645 is at position 1645, which is outside the BRCT domain (aa 1650-1857). Additionally, BayesDel score is -0.0818436, which is far below the 0.28 threshold. SpliceAI max delta is 0.02, below the 0.2 threshold for splicing-based PP3. Details ▾Hide ▴
Evidence considered
- Position 1645 is outside BRCT domain (aa 1650-1857)
- BayesDel no-AF: -0.0818436 (<0.28)
- SpliceAI max delta: 0.02 (<0.2)
Sources
bayesdelspliceai ↗
PP4 Variant is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. No PP4 LR data is available for this variant. Details ▾Hide ▴
Evidence considered
- Not found in Li 2020 BRCA1 clinical-history LR spreadsheet (PMID_31853058_BRCA1_clinical_history_LR.xlsx)
Still missing
- No clinical-history LR data for this variant
Sources
BA1 Variant is absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires filter allele frequency (FAF) >0.1% in a non-founder population. Not met. Details ▾Hide ▴
BS1 Variant is absent from gnomAD v2.1 and v4.1. ENIGMA BS1 Strong requires FAF >0.01%; BS1 Supporting requires FAF >0.002%. Not met. Details ▾Hide ▴
BP4 ENIGMA BP4 for missense variants explicitly requires location inside a clinically important functional domain with BayesDel <=0.15 and SpliceAI <=0.1. Arg1645 is outside the BRCT domain (aa 1650-1857), so the protein-change BP4 rule does not apply. SpliceAI is 0.02 but the splicing-based BP4 rule targets intronic variants outside donor/acceptor sites, not exonic missense. Details ▾Hide ▴
Evidence considered
- Position 1645 is outside BRCT domain
- BP4 protein-change rule not applicable
- BayesDel: -0.0818436
- SpliceAI: 0.02
Sources
PS5 No pathogenic missense variant has been established at residue Arg1645. All other substitutions at this residue are classified as BS3 (benign functional evidence) by ENIGMA Table 9. PS5 requires a previously established pathogenic variant at the same residue. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9: R1645G
- R1645K
- R1645T
- R1645M all assigned BS3 or no code
- no pathogenic comparator exists
Sources
vcep_specifications_table9_v1_2_2024_11_18
Not assessed · 6 · no assessment recorded
PS4 No case-control study with odds ratio and p-value is available for this variant. The variant has been observed in ClinVar and listed as a VUS in one Japanese HBOC cohort study (Arai 2018, PMID:29176636, n=1), but this does not meet the ENIGMA PS4 threshold (OR >=4, p<=0.05). Details ▾Hide ▴
Evidence considered
- Arai 2018: c.4935G>C listed as VUS in 1 Japanese proband (Table 4)
Still missing
- No case-control OR/p-value data available
Sources
PP1 No co-segregation data or likelihood ratio analysis is available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis (LR >=2.08 for Supporting). Details ▾Hide ▴
Still missing
- No segregation data available
BS2 No proband-level co-occurrence data or data on observation in healthy adults without Fanconi Anemia phenotype is available for this variant. ENIGMA BS2 requires point-based scoring per Specifications Table 8. Details ▾Hide ▴
Still missing
- No co-occurrence/healthy-adult observation data available
BS4 No segregation data or likelihood ratio analysis is available for this variant. ENIGMA BS4 requires quantitative co-segregation analysis showing lack of segregation (LR <=0.48 for Supporting). Details ▾Hide ▴
Still missing
- No segregation data available
BP5 Variant is not present in the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood ratio table. No BP5 LR data is available for this variant. Details ▾Hide ▴
Evidence considered
- Not found in Li 2020 BRCA1 clinical-history LR spreadsheet
Still missing
- No clinical-history LR data for this variant
Sources
BP7 No mRNA splicing assay data is available for this variant. ENIGMA BP7 requires well-established mRNA transcript profile data. SpliceAI predicts no splicing impact (delta 0.02), but BP7_Strong (RNA) requires direct mRNA assay evidence, not in silico prediction alone. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02
- no predicted splicing impact
Still missing
- No mRNA splicing assay data available
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (p.Arg1645Ser); PVS1 is restricted to null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion) per ENIGMA BRCA1 specification v1.2. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPENIGMA BRCA1 VCEP v1.2 deems PS2 not applicable for BRCA1/2. Details ▾Hide ▴
Sources
PM1 VCEPENIGMA BRCA1 VCEP v1.2 explicitly states PM1 is not applicable; considered as a component of bioinformatic analysis under PP3/BP4. Details ▾Hide ▴
Sources
PM5 N/AENIGMA BRCA1 VCEP v1.2 repurposes PM5 exclusively for protein termination codon (PTC) variants in exons where a proven pathogenic PTC has been observed. This is a missense variant and does not qualify for PM5_PTC logic. Details ▾Hide ▴
Sources
PM6 VCEPENIGMA BRCA1 VCEP v1.2 deems PM6 not applicable; BRCA1/2-related cancers occur relatively commonly and de novo occurrence cannot be calibrated. Details ▾Hide ▴
Sources
PP2 VCEPENIGMA BRCA1 VCEP v1.2 deems PP2 not applicable. Details ▾Hide ▴
Sources
PP5 VCEPENIGMA BRCA1 VCEP v1.2 deems PP5 not applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Sources
BP2 VCEPENIGMA BRCA1 VCEP v1.2 deems BP2 not applicable; applied only in the context of BS2. Details ▾Hide ▴
Sources
BP6 VCEPENIGMA BRCA1 VCEP v1.2 deems BP6 not applicable per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.4935G>C
- Protein (HGVS p.)
- NP_009225.1:p.(Arg1645Ser)
- GRCh38
- chr17:43070979 C>G
- GRCh37
- chr17:41222996 C>G
- ClinVar
- 868908, 868621, 867689, 867591, 865452, 865220, 55321, 868858
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.602
- BayesDel
- -0.082
How the predictions were used
PP3 PP3 for missense variants requires location inside a clinically important functional domain AND BayesDel no-AF score >=0.28. Arg1645 is at position 1645, which is outside the BRCT domain (aa 1650-1857). Additionally, BayesDel score is -0.0818436, which is far below the 0.28 threshold. SpliceAI max delta is 0.02, below the 0.2 threshold for splicing-based PP3. Details ▾Hide ▴
Evidence considered
- Position 1645 is outside BRCT domain (aa 1650-1857)
- BayesDel no-AF: -0.0818436 (<0.28)
- SpliceAI max delta: 0.02 (<0.2)
Sources
bayesdelspliceai ↗
BP4 ENIGMA BP4 for missense variants explicitly requires location inside a clinically important functional domain with BayesDel <=0.15 and SpliceAI <=0.1. Arg1645 is outside the BRCT domain (aa 1650-1857), so the protein-change BP4 rule does not apply. SpliceAI is 0.02 but the splicing-based BP4 rule targets intronic variants outside donor/acceptor sites, not exonic missense. Details ▾Hide ▴
Evidence considered
- Position 1645 is outside BRCT domain
- BP4 protein-change rule not applicable
- BayesDel: -0.0818436
- SpliceAI: 0.02
Sources
BP7 No mRNA splicing assay data is available for this variant. ENIGMA BP7 requires well-established mRNA transcript profile data. SpliceAI predicts no splicing impact (delta 0.02), but BP7_Strong (RNA) requires direct mRNA assay evidence, not in silico prediction alone. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.02
- no predicted splicing impact
Still missing
- No mRNA splicing assay data available
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.602. BayesDel score = -0.0818436.
9 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 30209399 ↗Accurate classification of BRCA1 variants with saturation genome editing.Findlay GM et al. · 2018 OctSaturation genome editing of BRCA1 exon 15 (BRCT domain region). c.4935G>C (p.Arg1645Ser) was classified as FUNC (functional, no damaging effect), indicating protein function similar to benign control variants.→ BS3 Names this variant
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PMID 30765603 ↗Impact of amino acid substitutions at secondary structures in the BRCT domains of the tumor suppressor BRCA1: Implications for clinical annotation.Fernandes VC et al. · 2019 Apr 12Functional characterization of amino acid substitutions in the BRCT domains of BRCA1. c.4935G>C (p.Arg1645Ser) was classified as Not Pathogenic based on integrated functional assay data.→ BS3 Names this variant
Other recorded publications
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PMID 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.ACMG/AMP 2015 standards and guidelines for interpretation of sequence variants. Provides the generic variant classification framework. NM_007294.4:c.4935G>C was not identified in this paper.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes the Sherloc variant scoring system for Mendelian disorders. NM_007294.4:c.4935G>C was not identified in this paper.Does not name this variant
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PMID 29176636 ↗Genetic and clinical characteristics in Japanese hereditary breast and ovarian cancer: first report after establishment of HBOC registration system in Japan.Arai M et al. · 2018Japanese HBOC registry study of 830 pedigrees. c.4935G>C (p.Arg1645Ser) listed in Table 4 as a variant of uncertain significance detected in one proband undergoing BRCA1/2 genetic testing.Names this variant
Quoted passage
5054G>C c.4935G>C p.Arg1645Ser 1
Table 4 (Variants of uncertain significance)
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PMID 10923033 ↗The breast cancer information core: database design, structure, and scope.Szabo C et al. · 2000Describes the Breast Cancer Information Core (BIC) database design and scope. NM_007294.4:c.4935G>C was not identified in this paper.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.National Society of Genetic Counselors practice recommendations for cancer genetic risk assessment and counseling. NM_007294.4:c.4935G>C was not identified in this paper.Does not name this variant
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PMID 16284991 ↗BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases.Pal T et al. · 2005Population-based study of BRCA1/2 mutations in 232 ovarian carcinoma cases. R1645S listed in a VUS table as a variant of uncertain significance in a patient of Central/Eastern European ancestry.Names this variant
Quoted passage
R1645S
VUS table listing
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Describes the Sherloc refinement of ACMG-AMP variant classification criteria. NM_007294.4:c.4935G>C was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
6 Uncertain significance · 3 Likely benign
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/55321/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41222996-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43070979-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43070979-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.4935…
- OncoKB ↗www.oncokb.org/gene/BRCA1/R1645S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.4935G%3EC
- 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
Absent from gnomAD v4.1.
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 (6 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 55321)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.602. BayesDel score = -0.0818436.
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.