About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.1534C>T, p.(Leu512Phe)
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BS1Supporting
BS1 · supporting
In gnomAD v2.1, the non-founder grpmax FAF is 8.82e-05, which is greater than the BS1_Supporting lower bound of 2e-05 and less than or equal to the BS1 threshold of 1e-04, supporting BS1_Supporting.
BS3Strong
BS3 · strong
Specifications Table 9 lists BRCA1 c.1534C>T (p.(Leu512Phe)) as BS3 Strong because one calibrated study reported protein function similar to benign control variants.
BP1Strong
BP1 · strong
Leu512 is outside the BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI is 0.00, which is less than or equal to the BP1_Strong splice threshold of 0.1; this supports BP1_Strong.
BP5Strong
BP5 · strong
Parsons supplementary data report a combined LR for causality of 0.007006151007218386, which is less than or equal to the ENIGMA BP5_Strong threshold of 0.05 and greater than the BP5_VeryStrong threshold of 0.00285, supporting BP5_Strong.
Recorded classification: Benign
Generic ACMG/AMP final classification combination rules were used as the fallback framework because no explicit VCEP-specific final combination table was retrieved into the workspace; under the retrieved generic rules, two Strong benign criteria support a Benign classification.
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
190 / 1,613,824 alleles
gnomAD v4.1: 190 / 1,613,824 alleles. Recorded AF 0.000117733. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.54321e-05; MAF= 0.00354%, 10/282230 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76627e-05; MAF= 0.00777%, 10/128762 alleles, homozygotes = 0); grpmax FAF= 8.82e-05.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 6 not met · 6 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
BRCA1 c.1534C>T (p.Leu512Phe, p.L512F) has been shown in a calibrated functional assay to have protein function similar to benign control variants, supporting BS3_Strong.
Multifactorial likelihood analysis yielded a combined LR for causality of 0.007006151007218386, which is below the ENIGMA BP5_Strong threshold of 0.05 and supports strong evidence against pathogenicity.
The gnomAD v2.1 non-founder grpmax FAF is 8.82e-05, which is within the BS1_Supporting range of >2e-05 to <=1e-04, and the missense change lies outside the BRCA1 clinically important domains with SpliceAI 0.00, supporting BS1_Supporting and BP1_Strong benign evidence.
Using the retrieved generic ACMG/AMP combination rules as fallback final-classification framework, the presence of at least two Strong benign criteria supports classification of this variant as Benign.
No criteria match.
Met · 4
BS1 SupportingIn gnomAD v2.1, the non-founder grpmax FAF is 8.82e-05, which is greater than the BS1_Supporting lower bound of 2e-05 and less than or equal to the BS1 threshold of 1e-04, supporting BS1_Supporting. Details ▾Hide ▴
Rule
BS1_Supporting when FAF >0.00002 and <=0.0001; BS1_Strong when FAF >0.0001.
Evidence considered
- gnomAD v2.1 grpmax FAF 8.82e-05
- Highest observed population European (non-Finnish), a non-founder population
Sources
BS3 StrongSpecifications Table 9 lists BRCA1 c.1534C>T (p.(Leu512Phe)) as BS3 Strong because one calibrated study reported protein function similar to benign control variants. Details ▾Hide ▴
Rule
BS3 applies when calibrated functional evidence shows no damaging effect.
Evidence considered
- Table 9 row: BS3 Strong
- Bouwman 2020 (PMID:32546644) listed as likely neutral
Sources
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
BP1 StrongLeu512 is outside the BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT aa 1650-1857), and SpliceAI is 0.00, which is less than or equal to the BP1_Strong splice threshold of 0.1; this supports BP1_Strong. Details ▾Hide ▴
Rule
BP1_Strong for missense/silent/in-frame variants outside clinically important domains with SpliceAI <=0.1.
Evidence considered
- Protein change p.(Leu512Phe) at aa 512
- Domain definitions from BRCA1 appendices
- SpliceAI max delta 0.00
Sources
BP5 StrongParsons supplementary data report a combined LR for causality of 0.007006151007218386, which is less than or equal to the ENIGMA BP5_Strong threshold of 0.05 and greater than the BP5_VeryStrong threshold of 0.00285, supporting BP5_Strong. Details ▾Hide ▴
Rule
BP5_Strong when combined LR <=0.05; BP5_VeryStrong when <=0.00285.
Evidence considered
- Combined LR 0.007006151007218386
- Posterior probability 0.0001429622324944735
- IARC Class Benign
Sources
cspec ↗vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
Not met · 6 · evaluated, threshold not reached
PS3 A calibrated BRCA1 functional assay assigned BS3 rather than PS3, reporting protein function similar to benign control variants. Details ▾Hide ▴
Rule
PS3 requires well-established damaging functional evidence.
Evidence considered
- Specifications Table 9 row: BRCA1 c.1534C>T p.(Leu512Phe) -> BS3 Strong
- Bouwman 2020 listed as likely neutral
Sources
vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_9___v_1___2___2_0_2_4___1_1___1_8
PM2 PM2_Supporting requires absence from gnomAD, but the variant is present in gnomAD v2.1 at AF 3.54321e-05 with grpmax FAF 8.82e-05 and in gnomAD v4.1 at AF 0.000117733. Details ▾Hide ▴
Rule
Absent from controls required for PM2_Supporting.
Evidence considered
- gnomAD v2.1 total AF 3.54321e-05; grpmax FAF 8.82e-05
- gnomAD v4.1 total AF 0.000117733
Sources
PP3 For BRCA1, PP3 applies to missense variants inside a clinically important domain with BayesDel no-AF score >=0.28 or to variants with SpliceAI >=0.2. Leu512 lies outside the BRCA1 RING, coiled-coil, and BRCT domains, and SpliceAI is 0.00, which is below the splice threshold of 0.2. Details ▾Hide ▴
Rule
PP3 requires domain-based BayesDel positivity or SpliceAI >=0.2.
Evidence considered
- Clinically important BRCA1 domains: aa 2-101, 1391-1424, 1650-1857
- Variant position Leu512
- SpliceAI max delta 0.00
Still missing
- No qualifying BayesDel domain-based evidence was retrieved for this outside-domain missense variant.
Sources
PP4 The multifactorial likelihood data retrieved for this variant are against pathogenicity rather than meeting the PP4 thresholds for combined clinical evidence toward pathogenicity. Details ▾Hide ▴
Rule
PP4 requires combined LR >=2.08 toward pathogenicity.
Evidence considered
- Combined LR 0.007006151007218386 in Parsons supplementary data
Sources
cspec ↗vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
BA1 BA1 requires a non-founder FAF >0.001. The gnomAD v2.1 grpmax FAF is 8.82e-05, which is below the BA1 threshold. Details ▾Hide ▴
Rule
BA1 requires FAF >0.001 in gnomAD v2.1/v3.1 non-founder population(s).
Evidence considered
- gnomAD v2.1 grpmax FAF 8.82e-05
Sources
BS4 The retrieved segregation LR is 0.99989998341, which is above the BS4_Supporting threshold of <=0.48 and therefore does not support lack of segregation. Details ▾Hide ▴
Rule
BS4 requires quantitative segregation LR <=0.48 at minimum supporting strength.
Evidence considered
- Segregation LR 0.99989998341 from Parsons supplementary data
Sources
cspec ↗vcep_h_u_m_u___4_0___1_5_5_7___s_0_0_1
Not assessed · 6 · no assessment recorded
PS1 No retrieved evidence established that another pathogenic or likely pathogenic variant produces the same amino-acid change or the same predicted splice effect required for PS1 weighting. Details ▾Hide ▴
Rule
Missense same-AA or splice-equivalent reference variant required.
Evidence considered
- ENIGMA BRCA1 PS1 rule requires same amino-acid or same splice effect as a classified pathogenic/likely pathogenic reference variant
Still missing
- No explicit same-amino-acid or same-splice reference variant was retrieved from the workspace.
Sources
PS4 No case-control dataset meeting the ENIGMA BRCA1 PS4 requirement of statistically increased prevalence in affected individuals was retrieved for this variant. Details ▾Hide ▴
Rule
Case-control OR and p-value thresholds required.
Evidence considered
- ENIGMA BRCA1 PS4 requires case-control enrichment with defined thresholds
Still missing
- No qualifying OR/p-value case-control evidence was retrieved.
Sources
PM3 No evidence of biallelic BRCA1-related Fanconi anemia with PM3 point assignment was retrieved. Details ▾Hide ▴
Rule
Fanconi-anemia-based point system required.
Evidence considered
- ENIGMA BRCA1 PM3 requires Fanconi anemia-specific biallelic evidence
Still missing
- No recessive disease proband data were retrieved.
Sources
PP1 No quantitative co-segregation evidence supporting pathogenicity was retrieved for PP1. Details ▾Hide ▴
Rule
Quantitative segregation LR threshold required.
Evidence considered
- ENIGMA BRCA1 PP1 requires quantitative segregation LR
Still missing
- No co-segregation LR favoring pathogenicity was retrieved.
Sources
BS2 No unaffected adult or recessive-disease exclusion dataset meeting the BRCA1 BS2 point-based framework was retrieved. Details ▾Hide ▴
Rule
Point-based BS2 framework required.
Evidence considered
- ENIGMA BRCA1 BS2 requires point-based evidence in absence of Fanconi anemia features
Still missing
- No BS2 point-assignment evidence was retrieved.
Sources
BP7 No mRNA assay evidence demonstrating a benign transcript profile was retrieved for this missense variant, so BP7 was not applied. Details ▾Hide ▴
Rule
RNA-based benign splicing evidence required for missense use.
Evidence considered
- BRCA1 BP7 requires mRNA-based benign splicing evidence or specific silent/intronic contexts
Still missing
- No qualifying RNA study for BP7 was retrieved.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007294.4:c.1534C>T is a missense substitution, p.(Leu512Phe), and is not a null, canonical splice-site, initiation-codon, or exon deletion variant. Details ▾Hide ▴
Rule
Apply only to LOF variant classes at VCEP-specified strengths.
Evidence considered
- Protein consequence p.(Leu512Phe)
- ENIGMA BRCA1 PVS1 rule applies to null/splice-site/initiation/canonical LOF events
Sources
PS2 N/APS2 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PS2 not applicable
Sources
PM1 N/APM1 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PM1 not applicable
Sources
PM4 N/APM4 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PM4 not applicable
Sources
PM5 N/AThe retrieved BRCA1 PM5 rule is PM5_PTC for protein-truncating variants in eligible exons, and c.1534C>T is a missense variant. Details ▾Hide ▴
Rule
BRCA1 PM5 applies to eligible PTC variants, not this missense change.
Evidence considered
- PM5 rule retrieved as PTC-specific in BRCA1
- Variant consequence is missense p.(Leu512Phe)
Sources
cspec ↗vcep_s_p_e_c_i_f_i_c_a_t_i_o_n_s___t_a_b_l_e_4___v_1___2___2_0_2_4___1_1___1_8
PM6 N/APM6 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PM6 not applicable
Sources
PP2 N/APP2 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PP2 not applicable
Sources
PP5 N/APP5 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: PP5 not applicable
Sources
BP2 N/ABP2 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: BP2 not applicable
Sources
BP3 N/ABP3 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: BP3 not applicable
Sources
BP4 N/AFor BRCA1 missense variants, BP4 applies inside a clinically important functional domain when BayesDel no-AF <=0.15 and SpliceAI <=0.1. This variant is outside the BRCA1 clinically important domains, so the missense BP4 rule is not the applicable benign in-silico pathway. Details ▾Hide ▴
Rule
BRCA1 missense BP4 is restricted to variants inside clinically important domains.
Evidence considered
- Variant position aa 512 outside RING/coiled-coil/BRCT domains
- BP4 missense rule is domain-limited in BRCA1
Sources
cspec ↗vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
BP6 N/ABP6 is designated not applicable in the retrieved BRCA1 VCEP specification. Details ▾Hide ▴
Rule
Not applicable per BRCA1 ENIGMA specification.
Evidence considered
- CSPEC applicability flag: BP6 not applicable
Sources
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.1534C>T
- Protein (HGVS p.)
- NP_009225.1:p.(Leu512Phe)
- GRCh38
- chr17:43093997 G>A
- GRCh37
- chr17:41246014 G>A
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
190 / 1,613,824 alleles
AF 0.000118 · 0 homozygotes · FAF 0.000132
gnomAD v2.1
10 / 282,230 alleles
AF 3.54e-05 · 0 homozygotes · FAF 8.82e-05
By genetic ancestry
gnomAD v4.1
AF 0.00012 · 190 / 1,613,824 alleles · 0 hom · FAF 0.00013
| Remaining individuals12 / 62,470 | 0.00019 |
| European (non-Finnish)178 / 1,179,972 | 0.00015 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Middle Eastern, South Asian, Ashkenazi Jewish, East Asian, African/African American, Amish.
gnomAD v2.1
AF 3.5e-05 · 10 / 282,230 alleles · 0 hom · FAF 8.8e-05
| European (non-Finnish)10 / 128,762 | 7.8e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000117733; MAF= 0.01177%, 190/1613824 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000192092; MAF= 0.01921%, 12/62470 alleles, homozygotes = 0); grpmax FAF= 0.00013243.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.54321e-05; MAF= 0.00354%, 10/282230 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76627e-05; MAF= 0.00777%, 10/128762 alleles, homozygotes = 0); grpmax FAF= 8.82e-05.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For BRCA1, PP3 applies to missense variants inside a clinically important domain with BayesDel no-AF score >=0.28 or to variants with SpliceAI >=0.2. Leu512 lies outside the BRCA1 RING, coiled-coil, and BRCT domains, and SpliceAI is 0.00, which is below the splice threshold of 0.2. Details ▾Hide ▴
Rule
PP3 requires domain-based BayesDel positivity or SpliceAI >=0.2.
Evidence considered
- Clinically important BRCA1 domains: aa 2-101, 1391-1424, 1650-1857
- Variant position Leu512
- SpliceAI max delta 0.00
Still missing
- No qualifying BayesDel domain-based evidence was retrieved for this outside-domain missense variant.
Sources
BP7 No mRNA assay evidence demonstrating a benign transcript profile was retrieved for this missense variant, so BP7 was not applied. Details ▾Hide ▴
Rule
RNA-based benign splicing evidence required for missense use.
Evidence considered
- BRCA1 BP7 requires mRNA-based benign splicing evidence or specific silent/intronic contexts
Still missing
- No qualifying RNA study for BP7 was retrieved.
Sources
BP4 N/AFor BRCA1 missense variants, BP4 applies inside a clinically important functional domain when BayesDel no-AF <=0.15 and SpliceAI <=0.1. This variant is outside the BRCA1 clinically important domains, so the missense BP4 rule is not the applicable benign in-silico pathway. Details ▾Hide ▴
Rule
BRCA1 missense BP4 is restricted to variants inside clinically important domains.
Evidence considered
- Variant position aa 512 outside RING/coiled-coil/BRCT domains
- BP4 missense rule is domain-limited in BRCA1
Sources
cspec ↗vcep_a_p_p_e_n_d_i_c_e_s___v_1___2___2_0_2_4___1_1___1_8
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
190 / 1,613,824 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
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/2823744/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41246014-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43093997-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.1534…
- OncoKB ↗www.oncokb.org/gene/BRCA1/L512F
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= 0.000117733; MAF= 0.01177%, 190/1613824 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000192092; MAF= 0.01921%, 12/62470 alleles, homozygotes = 0); grpmax FAF= 0.00013243.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.54321e-05; MAF= 0.00354%, 10/282230 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.76627e-05; MAF= 0.00777%, 10/128762 alleles, homozygotes = 0); grpmax FAF= 8.82e-05.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV58794737, n = 4 times).