About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.425C>A, p.(Pro142His)
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS1Strong
BS1 · strong
This variant exceeds the ENIGMA BS1 threshold for benign population frequency. The highest observed filter allele frequency is 0.00015726 in gnomAD v2.1 and 0.00015364 in gnomAD v4.1, both above the BS1_Strong cutoff of >0.0001.
BS3Strong
BS3 · strong
Calibrated functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3_Strong to BRCA1 c.425C>A (p.Pro142His), and supplementary functional data describe this variant as having no functional impact.
BP1Strong
BP1 · strong
This missense variant is outside the BRCA1 clinically important functional domains and has no predicted splice effect. p.Pro142His is outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, and SpliceAI shows a maximum delta score of 0.00, which is below the ≤0.1 threshold; this supports BP1_Strong.
Recorded classification: Benign
Official ClinGen ENIGMA BRCA1/BRCA2 specification v1.2.0 final-classification framework was used, applying Table 3 criteria-combination rules.
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
91 / 1,613,662 alleles
gnomAD v4.1: 91 / 1,613,662 alleles. Recorded AF 5.63935e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.57746e-05; MAF= 0.00958%, 27/281912 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000283752; MAF= 0.02838%, 10/35242 alleles, homozygotes = 0); grpmax FAF= 0.00015726.
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 classifies this variant as Likely Neutral; biological effect: Likely Neutral.
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 3 met · 4 not met · 9 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
The BRCA1 c.425C>A (p.Pro142His) variant has been reported in ClinVar with an ENIGMA expert panel benign classification.
This variant is present in gnomAD, and the highest observed filter allele frequencies exceed the ENIGMA BS1_Strong threshold of 0.0001 (gnomAD v2.1 grpmax FAF 0.00015726; gnomAD v4.1 joint grpmax FAF 0.00015364).
Calibrated BRCA1 functional evidence supports no damaging effect, with ENIGMA Table 9 assigning BS3_Strong and supplementary functional data describing no functional impact.
This missense change is outside the BRCA1 clinically important functional domains, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is consistent with BP1_Strong and does not support PP3.
No criteria match.
Met · 3
BS1 StrongThis variant exceeds the ENIGMA BS1 threshold for benign population frequency. The highest observed filter allele frequency is 0.00015726 in gnomAD v2.1 and 0.00015364 in gnomAD v4.1, both above the BS1_Strong cutoff of >0.0001. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BS1 Strong: FAF >0.0001 in gnomAD non-founder population(s).
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00015726 (>0.0001).
- gnomAD v4.1 joint grpmax FAF 0.00015364 (>0.0001).
Sources
BS3 StrongCalibrated functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3_Strong to BRCA1 c.425C>A (p.Pro142His), and supplementary functional data describe this variant as having no functional impact. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BS3 Strong: calibrated functional studies show no damaging effect on protein function.
Evidence considered
- ENIGMA Table 9 lists BS3 Strong for c.425C>A.
- Supplementary functional data list c.425C>A as no functional impact.
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_8vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8
BP1 StrongThis missense variant is outside the BRCA1 clinically important functional domains and has no predicted splice effect. p.Pro142His is outside the RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains, and SpliceAI shows a maximum delta score of 0.00, which is below the ≤0.1 threshold; this supports BP1_Strong. Details ▾Hide ▴
Rule
ENIGMA BRCA1/2 BP1 Strong: missense variant outside clinically important functional domain with SpliceAI <=0.1.
Evidence considered
- p.Pro142His is outside the BRCA1 clinically important domains defined by ENIGMA.
- SpliceAI max delta score 0.00 (<=0.1).
Sources
Not met · 4 · evaluated, threshold not reached
PS3 Available calibrated functional evidence does not support a damaging effect. ENIGMA Table 9 assigns BS3_Strong for this variant, and supplementary functional data describe no functional impact rather than loss of function. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 9 lists BRCA1 c.425C>A p.(Pro142His) as BS3 Strong.
- Supplementary functional data list c.425C>A as having no functional impact.
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_8vcep_s_u_p_p_l_e_m_e_n_t_a_r_y_t_a_b_l_e_s___v_1___2___2_0_2_4___1_1___1_8
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000958 (27/281912) and in gnomAD v4.1 at AF 0.0000564 (91/1613662), so the ENIGMA PM2 absence criterion is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 0.0000958
- 27/281912 alleles.
- gnomAD v4.1 total AF 0.0000564
- 91/1613662 alleles.
Sources
PP3 Computational evidence does not meet the ENIGMA PP3 thresholds. SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the ≥0.2 splicing threshold, and the variant lies outside the BRCA1 clinically important functional domains required for missense PP3 application. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- BRCA1 clinically important domains are RING aa 2-101
- coiled-coil aa 1391-1424
- and BRCT aa 1650-1857
- p.Pro142His is outside these regions.
Sources
BA1 Population data do not reach the ENIGMA BA1 threshold. The highest observed filter allele frequencies are 0.00015726 in gnomAD v2.1 and 0.00015364 in gnomAD v4.1, both below the BA1 cutoff of >0.001. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00015726.
- gnomAD v4.1 joint grpmax FAF 0.00015364.
Sources
Not assessed · 9 · no assessment recorded
PS1 No previously classified pathogenic or likely pathogenic variant with the same predicted amino acid change or the same predicted splice effect was identified in the reviewed sources, so PS1 was not applied. Details ▾Hide ▴
PS4 No case-control study or quantitative affected-versus-control comparison meeting the ENIGMA PS4 threshold was identified, so PS4 was not applied. Details ▾Hide ▴
PM3 No evidence of BRCA1-related Fanconi anemia with a qualifying in-trans second BRCA1 variant was identified, so PM3 was not applied. Details ▾Hide ▴
Evidence considered
- The BRCA1 PM3 rule requires Fanconi anemia-related phenotype and point-based in-trans evidence.
Still missing
- No recessive disease phenotype or phase data were available.
Sources
PP1 No quantitative co-segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
PP4 No multifactorial clinical likelihood ratio meeting the ENIGMA PP4 thresholds was identified, so PP4 was not applied. Details ▾Hide ▴
Evidence considered
- The BRCA1 PP4 rule is based on quantitative multifactorial likelihood ratios.
Still missing
- No qualifying clinical LR dataset was available.
Sources
BS2 No point-based BS2 evidence from unaffected individuals without Fanconi anemia features was identified, so BS2 was not applied. Details ▾Hide ▴
Evidence considered
- The BRCA1 BS2 rule requires point-based evaluation in the absence of recessive disease features.
Still missing
- No qualifying proband-level BS2 dataset was available.
Sources
BS4 No quantitative lack-of-segregation dataset was identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Evidence considered
- The BRCA1 BS4 rule requires quantitative non-segregation evidence.
Still missing
- No segregation likelihood ratio against pathogenicity was available.
Sources
BP5 No multifactorial likelihood ratio against pathogenicity meeting the ENIGMA BP5 thresholds was identified, so BP5 was not applied. Details ▾Hide ▴
Evidence considered
- The BRCA1 BP5 rule is based on quantitative multifactorial likelihood ratios.
Still missing
- No qualifying BP5 likelihood ratio was available.
Sources
BP7 No RNA study showing a benign transcript effect was identified for this missense variant, so BP7 was not applied. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no significant splice effect
- but no BP7-qualifying RNA assay was identified.
Still missing
- No qualifying mRNA assay result was available.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical ±1/2 splice, initiation-codon, or exon-level loss-of-function variant, so PVS1 does not apply. Details ▾Hide ▴
Evidence considered
- BRCA1 loss of function is an established disease mechanism in the ENIGMA BRCA1 framework.
- The variant-specific PVS1 assessment states that c.425C>A is not in a default null-variant bucket.
Sources
PS2 N/AThe ENIGMA BRCA1 specification does not use PS2 for this VCEP framework. Details ▾Hide ▴
PM1 N/APM1 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
PM4 N/APM4 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
PM5 N/AIn the ENIGMA BRCA1 framework, PM5 is used for protein-truncating variants already annotated with PVS1. This missense variant does not meet that context, so PM5 does not apply. Details ▾Hide ▴
Evidence considered
- The ENIGMA PM5 rule shown in the reviewed materials is for PTC variants in applicable exons.
- c.425C>A is a missense variant.
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/AThe ENIGMA BRCA1 specification does not use PM6 for this VCEP framework. Details ▾Hide ▴
PP2 N/APP2 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
PP5 N/APP5 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
BP2 N/ABP2 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
BP3 N/ABP3 is not used in the ENIGMA BRCA1 specification. Details ▾Hide ▴
BP4 N/AFor BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. p.Pro142His is outside those domains, so BP4 does not apply in this framework. Details ▾Hide ▴
Evidence considered
- The ENIGMA BP4 missense rule is limited to variants inside defined BRCA1 functional domains.
- p.Pro142His is outside the defined BRCA1 functional domains.
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/AThe ENIGMA BRCA1 specification does not use BP6 for this VCEP framework. Details ▾Hide ▴
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.425C>A
- Protein (HGVS p.)
- NP_009225.1:p.(Pro142His)
- GRCh38
- chr17:43104138 G>T
- GRCh37
- chr17:41256155 G>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
91 / 1,613,662 alleles
AF 5.64e-05 · 0 homozygotes · FAF 0.000154
gnomAD v2.1
27 / 281,912 alleles
AF 9.58e-05 · 0 homozygotes · FAF 0.000157
By genetic ancestry
gnomAD v4.1
AF 5.6e-05 · 91 / 1,613,662 alleles · 0 hom · FAF 0.00015
| Admixed American15 / 59,966 | 0.00025 |
| Middle Eastern1 / 6,082 | 0.00016 |
| Remaining individuals10 / 62,474 | 0.00016 |
| European (non-Finnish)64 / 1,179,892 | 5.4e-05 |
| South Asian1 / 91,000 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 9.6e-05 · 27 / 281,912 alleles · 0 hom · FAF 0.00016
| Admixed American10 / 35,242 | 0.00028 |
| Remaining individuals2 / 7,192 | 0.00028 |
| European (non-Finnish)15 / 128,916 | 0.00012 |
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.63935e-05; MAF= 0.00564%, 91/1613662 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000250142; MAF= 0.02501%, 15/59966 alleles, homozygotes = 0); grpmax FAF= 0.00015364.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.57746e-05; MAF= 0.00958%, 27/281912 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000283752; MAF= 0.02838%, 10/35242 alleles, homozygotes = 0); grpmax FAF= 0.00015726.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Computational evidence does not meet the ENIGMA PP3 thresholds. SpliceAI predicts no splice effect with a maximum delta score of 0.00, which is below the ≥0.2 splicing threshold, and the variant lies outside the BRCA1 clinically important functional domains required for missense PP3 application. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.00.
- BRCA1 clinically important domains are RING aa 2-101
- coiled-coil aa 1391-1424
- and BRCT aa 1650-1857
- p.Pro142His is outside these regions.
Sources
BP7 No RNA study showing a benign transcript effect was identified for this missense variant, so BP7 was not applied. Details ▾Hide ▴
Evidence considered
- SpliceAI predicts no significant splice effect
- but no BP7-qualifying RNA assay was identified.
Still missing
- No qualifying mRNA assay result was available.
Sources
BP4 N/AFor BRCA1 missense variants, BP4 is reserved for variants inside a clinically important functional domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. p.Pro142His is outside those domains, so BP4 does not apply in this framework. Details ▾Hide ▴
Evidence considered
- The ENIGMA BP4 missense rule is limited to variants inside defined BRCA1 functional domains.
- p.Pro142His is outside the defined BRCA1 functional domains.
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
91 / 1,613,662 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
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/41823/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41256155-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43104138-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.425C…
- OncoKB ↗www.oncokb.org/gene/BRCA1/P142H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=144960749
- 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= 5.63935e-05; MAF= 0.00564%, 91/1613662 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000250142; MAF= 0.02501%, 15/59966 alleles, homozygotes = 0); grpmax FAF= 0.00015364.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.57746e-05; MAF= 0.00958%, 27/281912 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000283752; MAF= 0.02838%, 10/35242 alleles, homozygotes = 0); grpmax FAF= 0.00015726.
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB classifies this variant as Likely Neutral; biological effect: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99070445, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.