About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.4720G>T, p.(Asp1574Tyr)
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
The variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in outbred populations, meeting ENIGMA PM2_Supporting criteria for absent from controls.
Benign criteria applied · 1
BP1Strong
BP1 · strong
ENIGMA BP1_Strong applies to missense variants located outside all clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). p.Asp1574Tyr lies at amino acid 1574, outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. SpliceAI max delta score is 0.02 (≤0.1), confirming no predicted splice impact.
Recorded classification: Likely benign
ENIGMA BRCA1/2 v1.2.0 Table 3 point system for conflicting evidence: PM2_Supporting (+1) + BP1_Strong (-4) = -3 total points. Score of -3 falls in the Likely Benign range (-6 to -2). The variant has only one met criterion on each side (1 supporting pathogenic, 1 strong benign), triggering the ENIGMA conflicting-evidence point-based resolution rather than a simple all_of table match.
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.
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
1 reported laboratory submissions
1 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: 2 met · 9 not met · 5 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.4720G>T (p.Asp1574Tyr) is a missense variant in BRCA1 exon 15, located outside all three clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). It is absent from gnomAD v2.1 and v4.1 population databases.
The variant meets PM2_Supporting: absent from gnomAD controls in outbred populations, per ENIGMA specifications.
The variant meets BP1_Strong: missense substitution outside clinically important functional domains with no predicted splicing impact (SpliceAI max delta 0.02). Per ENIGMA Figure 1A, missense variants outside domains with SpliceAI ≤0.1 receive BP1_Strong.
PVS1, PS1, PM5, and several other criteria are not applicable as this is a missense variant without a same-residue pathogenic comparator and without null-variant features.
PS3 could not be assessed through the ENIGMA framework as the variant is not listed in Table 9 (calibrated functional assays). External functional evidence (Carvalho 2007 PMID:17308087, Starita 2018 PMID:29892012) suggests a damaging effect in yeast transcription and multiplex HDR assays, but these have not been calibrated through ENIGMA standards. Human review is recommended.
PP4 and BP5 could not be assessed: the variant is absent from the Li et al. 2020 (PMID:31853058) BRCA1 clinical-history likelihood-ratio table.
PS4, PP1, BS2, BS4, and BP7 have no supporting evidence available for this variant. BS3 is not met as functional evidence points toward damaging effect rather than benign.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 (non-cancer, exome only) and gnomAD v4.1 (non-cancer) in outbred populations, meeting ENIGMA PM2_Supporting criteria for absent from controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exome)
- Absent from gnomAD v4.1
Still missing
- Read depth at variant position not explicitly verified (ENIGMA requires ≥25x)
Sources
BP1 StrongENIGMA BP1_Strong applies to missense variants located outside all clinically important functional domains with no predicted splicing impact (SpliceAI ≤0.1). p.Asp1574Tyr lies at amino acid 1574, outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. SpliceAI max delta score is 0.02 (≤0.1), confirming no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant at aa 1574 outside all three BRCA1 functional domains
- SpliceAI 0.02 (≤0.1 threshold)
- BayesDel 0.109 (confirmatory)
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No known pathogenic or likely pathogenic missense variant has been identified at the same amino acid residue (Asp1574) to serve as a comparator. The pm5_candidates search identified zero same-residue candidates with expert panel pathogenic classification. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator at residue 1574 identified in ClinVar or ENIGMA datasets
Sources
pm5_candidatescspec ↗
PS4 ENIGMA PS4 requires case-control data with p≤0.05 and OR≥4 (lower CI excludes 2.0). No case-control study or cohort analysis demonstrating enrichment of this variant in affected individuals versus controls is available. The variant is absent from gnomAD population databases, consistent with rarity, but this alone does not satisfy PS4. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- No case-control or cohort enrichment data available
Still missing
- No case-control
- cohort enrichment
- or BRCA Exchange aggregated case data
Sources
PP1 ENIGMA PP1 requires quantitative cosegregation analysis demonstrating co-segregation with disease in multiple affected family members (LR≥2.08 for supporting). No published cosegregation data involving this variant was identified. Details ▾Hide ▴
Evidence considered
- No cosegregation studies identified for this variant
Still missing
- No family-based cosegregation data available
Sources
PP3 ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel ≥0.28, or variants with SpliceAI ≥0.2 irrespective of domain location. p.Asp1574Tyr lies outside all BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), BayesDel no-AF score is 0.109 (<0.28), and SpliceAI max delta is 0.02 (<0.2). Neither condition for PP3 is met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.109 (<0.28 threshold)
- SpliceAI 0.02 (<0.2 threshold)
- aa 1574 outside clinically important functional domains
Sources
BA1 ENIGMA BA1 requires filter allele frequency (FAF) above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome) and/or gnomAD v3.1 (non-cancer). The variant is absent from gnomAD v2.1 and v4.1. BA1 is not met. Details ▾Hide ▴
BS1 ENIGMA BS1 requires FAF > 0.01% (strong) or FAF > 0.002% and ≤ 0.01% (supporting) in gnomAD non-founder populations. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met. Details ▾Hide ▴
BS3 ENIGMA BS3 requires well-established functional studies showing no damaging effect on protein function. The variant is not listed in ENIGMA Table 9 with a BS3 assignment. External functional evidence (Carvalho et al. 2007 PMID:17308087; Starita et al. 2018 PMID:29892012) indicates a damaging rather than benign functional effect. BS3 is not met; the available evidence points in the opposite direction (damaging). Details ▾Hide ▴
Evidence considered
- Not present in ENIGMA Table 9
- Functional studies show damaging effect
- not benign
Sources
BP4 ENIGMA BP4 (supporting benign from computational evidence) applies to missense variants inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Since p.Asp1574Tyr lies outside all BRCA1 functional domains, the primary BP4 rule for missense variants is not triggered. Although BayesDel (0.109) and SpliceAI (0.02) both fall below the specified thresholds, the domain location requirement is not satisfied. Details ▾Hide ▴
Evidence considered
- BayesDel 0.109 (≤0.15)
- SpliceAI 0.02 (≤0.1)
- aa 1574 outside functional domains
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established mRNA assay data demonstrating no splicing aberration. ENIGMA BP7_Supporting applies to silent/intronic variants under specific conditions, not to missense variants outside functional domains. No mRNA transcript analysis data were identified for this variant. SpliceAI prediction alone is insufficient to meet BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI 0.02 (no predicted splicing impact)
- No mRNA assay data available
- BP7 rules not triggered for missense outside domain without RNA data
Still missing
- No mRNA transcript analysis for this variant
Sources
Not assessed · 5 · no assessment recorded
PS3 ENIGMA PS3 rule directs to Specifications Table 9 for calibrated functional assay code assignment. c.4720G>T is not listed in Table 9 and no ENIGMA-pre-assigned PS3 code exists. External functional evidence was identified (Carvalho et al. 2007 PMID:17308087 reported impaired transcription in yeast assay; Starita et al. 2018 PMID:29892012 reported reduced HDR activity in multiplex assay), but these assays have not been calibrated through the ENIGMA framework. Human review is required to determine if these functional studies meet ENIGMA PS3 calibration standards. Details ▾Hide ▴
Evidence considered
- Not present in ENIGMA Table 9
- Carvalho 2007 yeast transcription assay: deleterious (PMID:17308087)
- Starita 2018 multiplex HDR assay: functionally deleterious (PMID:29892012)
Still missing
- External functional studies not calibrated through ENIGMA framework
- need expert review for PS3 code assignment
Sources
PP4 ENIGMA PP4 uses calibrated clinical-history likelihood ratios from Li et al. 2020 (PMID:31853058). The variant NM_007294.4:c.4720G>T was not found in the BRCA1 clinical_history_LR table. No alternative multifactorial clinical likelihood data are available. PP4 cannot be assessed without variant-specific LR data. Details ▾Hide ▴
Evidence considered
- Variant not present in Li et al. 2020 BRCA1 clinical-history LR table
Still missing
- No clinical-history LR data available for this variant
Sources
BS2 ENIGMA BS2 requires observation in healthy adults without features of Fanconi anemia. No data on observations of this variant in healthy adult controls beyond gnomAD absence were identified. BS2 cannot be assessed without dedicated control cohort data. Details ▾Hide ▴
Evidence considered
- No data on variant observation in healthy adult controls beyond population databases
Still missing
- No healthy adult control cohort data specific to this variant
Sources
BS4 ENIGMA BS4 requires quantitative lack-of-segregation data (LR ≤0.48 for supporting, ≤0.23 for moderate, ≤0.05 for strong). No segregation data of any kind were identified for this variant. BS4 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family segregation studies for this variant
Sources
BP5 ENIGMA BP5 uses calibrated clinical-history likelihood ratios from Li et al. 2020 (PMID:31853058). The variant NM_007294.4:c.4720G>T was not found in the BRCA1 clinical_history_LR table. No alternative multifactorial clinical likelihood data are available. BP5 cannot be assessed without variant-specific LR data. Details ▾Hide ▴
Evidence considered
- Variant not present in Li et al. 2020 BRCA1 clinical-history LR table
Still missing
- No clinical-history LR data available for this variant
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.4720G>T is a missense substitution (p.Asp1574Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). SpliceAI max delta score is 0.02, excluding splicing-related PVS1 (RNA). ENIGMA BRCA1 Table 4 PVS1 rules apply only to null/splice variants in exon 15; missense variants are not eligible. Details ▾Hide ▴
Evidence considered
- Missense variant in exon 15
- SpliceAI max delta 0.02 (no splicing impact)
- ENIGMA Table 4 PVS1 restricted to null/splice variants
Sources
PS2 VCEPENIGMA BRCA1/2 specification v1.2.0 declares PS2 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
PM1 VCEPENIGMA BRCA1/2 specification v1.2.0 declares PM1 not applicable. Additionally, the variant resides at amino acid 1574, which lies outside all three BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857). Details ▾Hide ▴
Evidence considered
- ENIGMA CSPEC PM1 applicability: Not Applicable
- aa 1574 outside RING (2-101)
- coiled-coil (1391-1424)
- and BRCT (1650-1857) domains
Sources
PM5 N/AENIGMA repurposes PM5 as PM5_PTC, applicable only to protein-truncating codon (PTC) variants that already meet PVS1, to provide additional weight based on exon-level PTC prevalence. c.4720G>T is a missense variant (p.Asp1574Tyr) and does not qualify as a PTC. Classic same-residue missense PM5 is not used in the ENIGMA framework. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a PTC
- PM5_PTC mode only per ENIGMA
Sources
pm5_candidatescspec ↗
PM6 VCEPENIGMA BRCA1/2 specification v1.2.0 declares PM6 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
PP2 VCEPENIGMA BRCA1/2 specification v1.2.0 declares PP2 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
PP5 VCEPENIGMA BRCA1/2 specification v1.2.0 declares PP5 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
BP2 VCEPENIGMA BRCA1/2 specification v1.2.0 declares BP2 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
BP6 VCEPENIGMA BRCA1/2 specification v1.2.0 declares BP6 not applicable for BRCA1/BRCA2 variant interpretation. Details ▾Hide ▴
PS5 N/APS5 is not included in the ENIGMA BRCA1/2 specification v1.2.0 criteria set. This criterion is not used by the governing VCEP framework. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.4720G>T
- Protein (HGVS p.)
- NP_009225.1:p.(Asp1574Tyr)
- GRCh38
- chr17:43071194 C>A
- GRCh37
- chr17:41223211 C>A
- ClinVar
- 1743673, 1721423, 936973, 868861, 868575, 868409, 848155, 825189, 55317
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.604
- BayesDel
- 0.109
How the predictions were used
PP3 ENIGMA PP3 applies to missense variants inside a clinically important functional domain with BayesDel ≥0.28, or variants with SpliceAI ≥0.2 irrespective of domain location. p.Asp1574Tyr lies outside all BRCA1 functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), BayesDel no-AF score is 0.109 (<0.28), and SpliceAI max delta is 0.02 (<0.2). Neither condition for PP3 is met. Details ▾Hide ▴
Evidence considered
- BayesDel 0.109 (<0.28 threshold)
- SpliceAI 0.02 (<0.2 threshold)
- aa 1574 outside clinically important functional domains
Sources
BP4 ENIGMA BP4 (supporting benign from computational evidence) applies to missense variants inside a clinically important functional domain with BayesDel ≤0.15 AND SpliceAI ≤0.1. Since p.Asp1574Tyr lies outside all BRCA1 functional domains, the primary BP4 rule for missense variants is not triggered. Although BayesDel (0.109) and SpliceAI (0.02) both fall below the specified thresholds, the domain location requirement is not satisfied. Details ▾Hide ▴
Evidence considered
- BayesDel 0.109 (≤0.15)
- SpliceAI 0.02 (≤0.1)
- aa 1574 outside functional domains
Sources
BP7 ENIGMA BP7_Strong (RNA) requires well-established mRNA assay data demonstrating no splicing aberration. ENIGMA BP7_Supporting applies to silent/intronic variants under specific conditions, not to missense variants outside functional domains. No mRNA transcript analysis data were identified for this variant. SpliceAI prediction alone is insufficient to meet BP7. Details ▾Hide ▴
Evidence considered
- SpliceAI 0.02 (no predicted splicing impact)
- No mRNA assay data available
- BP7 rules not triggered for missense outside domain without RNA data
Still missing
- No mRNA transcript analysis for this variant
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.604. BayesDel score = 0.108762.
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.Phillips KA et al. · 2013No paper-specific finding is recorded.
-
PMID 12692171 ↗American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.American Society of Clinical Oncology · 2003No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
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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. · 2007No paper-specific finding is recorded.
-
PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 19305347 ↗ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.2009No paper-specific finding is recorded.
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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. · 2010No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
1 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/936973/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41223211-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43071194-C-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.4720…
- OncoKB ↗www.oncokb.org/gene/BRCA1/D1574Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.4720G%3ET
- 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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 936973)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.604. BayesDel score = 0.108762.
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.