About BRCA1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRCA1 c.738del, p.(Asn247ThrfsTer51)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_007294.4:c.738del is a frameshift deletion in BRCA1 exon 10 that creates a premature termination codon at p.(Asn247ThrfsTer51). Loss of function is an established disease mechanism for BRCA1. Under ENIGMA Specifications Table 4, PTC variants in exon 10 are assigned PVS1 at full strength. The truncation occurs early in the coding sequence (codon 247 of 1864), far upstream of the clinically important BRCT domains (aa 1650-1857), and is expected to trigger nonsense-mediated decay.
PM5Strong
PM5 · strong
Under ENIGMA Specifications Table 4, PTC variants in BRCA1 exon 10 are assigned PM5_Strong (PTC). This criterion provides additional weight for protein termination codon variants in exons where proven pathogenic PTC variants have been previously observed. BRCA1 exon 10 is the largest coding exon and contains numerous established pathogenic PTC variants.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
ENIGMA BRCA1/BRCA2 v1.2 Table 3: 1 Very Strong criterion (PVS1) plus 1 Strong criterion (PM5) satisfies the Pathogenic combination rule. PVS1 assigned for frameshift deletion NM_007294.4:c.738del creating a premature termination codon (p.Asn247ThrfsTer51) in BRCA1 exon 10, an established loss-of-function disease mechanism. PM5 assigned at Strong weight per ENIGMA Table 4 for PTC variants in exon 10. No benign criteria are met; no conflicting evidence is present.
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.
No listed criterion applied
SpliceAI score
0.150 maximum delta
Recorded SpliceAI maximum delta score: 0.150. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
29 criteria with recorded statuses: 2 met · 2 not met · 6 not assessed · 19 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.738del (p.Asn247ThrfsTer51) is a frameshift deletion in BRCA1 exon 10 predicted to produce a premature termination codon and trigger nonsense-mediated decay.
PVS1 (Very Strong) is assigned per ENIGMA Specifications Table 4: PTC variants in BRCA1 exon 10 receive full PVS1 weight.
PM5_Strong (PTC) is assigned per ENIGMA Specifications Table 4: BRCA1 exon 10 PTC variants receive PM5_Strong under the PTC-specific PM5 framework.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. PM2 is not applicable per ENIGMA rules — deletions are excluded from PM2 application.
ENIGMA criteria PS2/PM6, PS3/BS3 (Table 9), PM1, PM4, PP2, PP3, BP1, BP3, BP4, BP7, BP2, PP5, and BP6 are not applicable to this frameshift variant under the ENIGMA v1.2 specification framework.
No publications with variant-specific evidence for NM_007294.4:c.738del were identified in the literature review. Seven full-text papers and associated abstracts were reviewed; none mention this exact variant.
No criteria match.
Met · 2
PVS1 Very strongNM_007294.4:c.738del is a frameshift deletion in BRCA1 exon 10 that creates a premature termination codon at p.(Asn247ThrfsTer51). Loss of function is an established disease mechanism for BRCA1. Under ENIGMA Specifications Table 4, PTC variants in exon 10 are assigned PVS1 at full strength. The truncation occurs early in the coding sequence (codon 247 of 1864), far upstream of the clinically important BRCT domains (aa 1650-1857), and is expected to trigger nonsense-mediated decay. Details ▾Hide ▴
Evidence considered
- ENIGMA BRCA1 Table 4: exon 10 PTC row assigns PVS1 (full strength)
- Frameshift variant creating PTC at codon 247
- predicted to undergo NMD
- BRCA1 LoF is established disease mechanism per ENIGMA
Sources
vcep_specifications_table4_v1_2_2024_11_18cspec ↗
PM5 StrongUnder ENIGMA Specifications Table 4, PTC variants in BRCA1 exon 10 are assigned PM5_Strong (PTC). This criterion provides additional weight for protein termination codon variants in exons where proven pathogenic PTC variants have been previously observed. BRCA1 exon 10 is the largest coding exon and contains numerous established pathogenic PTC variants. Details ▾Hide ▴
Evidence considered
- ENIGMA Table 4 Column L: exon 10 PTC row assigns PM5_Strong (PTC)
- Exon 10 is the largest BRCA1 exon with many proven pathogenic truncating variants
Sources
vcep_specifications_table4_v1_2_2024_11_18cspec ↗
Not met · 2 · evaluated, threshold not reached
BA1 BA1 requires filter allele frequency >0.1% in gnomAD non-founder populations. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 threshold is not satisfied. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (non-cancer exomes)
- Absent from gnomAD v4.1 (non-cancer)
- Absent from gnomAD-Canada v1.0
Sources
BS1 BS1 requires FAF>0.01% (Strong) or FAF>0.002% (Supporting) in gnomAD non-founder populations. The variant is absent from all gnomAD datasets. Neither BS1 threshold is satisfied. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
Sources
Not assessed · 6 · no assessment recorded
PS4 No case-control data meeting ENIGMA PS4 criteria (p≤0.05, OR≥4, CI excludes 2.0) was identified for this variant. The variant is absent from gnomAD population datasets, precluding a case-control comparison from available data. Details ▾Hide ▴
Still missing
- No case-control study or enriched-cohort data available for this variant
PP1 No co-segregation data meeting ENIGMA PP1 criteria (quantitative Bayes score LR≥2.08) is available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation analysis or family-based pedigree data available
PP4 No clinical-history likelihood ratio data is available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 clinical_history_LR table. The variant c.738del was not found in the table, precluding PP4/BP5 assessment via this calibrated dataset. Details ▾Hide ▴
Evidence considered
- Variant not present in Li et al. 2020 clinical_history_LR table for BRCA1
Still missing
- No calibrated clinical-history LR data available for this specific variant
Sources
BS2 BS2 requires evidence of co-occurrence with a pathogenic variant in the absence of Fanconi anemia features. No proband-level co-occurrence data is available for this variant. Details ▾Hide ▴
Still missing
- No homozygous or compound heterozygous observations available
BS4 No lack-of-segregation data meeting ENIGMA BS4 criteria (quantitative Bayes score LR≤0.48) is available for this variant. Details ▾Hide ▴
Still missing
- No segregation or non-segregation pedigree data available
BP5 No clinical-history likelihood ratio data is available for this variant in the Li et al. 2020 (PMID:31853058) BRCA1 clinical_history_LR table. Variant not found in the calibrated dataset. Details ▾Hide ▴
Evidence considered
- Variant not present in Li et al. 2020 clinical_history_LR table for BRCA1
Still missing
- No calibrated clinical-history LR data available for this specific variant
Sources
Not applicable · 19· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense substitutions or splicing variants with the same predicted impact as a previously classified pathogenic variant. This is a frameshift deletion, not a missense or splicing variant. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPENIGMA v1.2 specifies PM6 (and PS2) are not applicable for BRCA1/2: BRCA1/2-related cancers are relatively common and there is no information to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴
No further detail was recorded.
PS3 N/AENIGMA Table 9 functional assay assignments apply to missense and synonymous variants only. This is a frameshift variant; functional assessment is captured through PVS1 per the ENIGMA framework. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPPM1 is not applicable per ENIGMA v1.2; mutational hotspot and functional domain evidence is considered as a component of bioinformatic analysis (PP3/BP4). Details ▾Hide ▴
No further detail was recorded.
PM2 N/AENIGMA v1.2 specifies: 'Do not apply for insertion, deletion or delins variants.' This variant is a single-nucleotide deletion; PM2 is excluded by VCEP rule regardless of gnomAD absence. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- ENIGMA rule explicitly excludes deletions from PM2 application
Sources
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPPM4 is not applicable per ENIGMA v1.2; protein length changes due to in-frame deletions/insertions are captured under the PP3/BP4 bioinformatic framework. This variant is a frameshift, not an in-frame change. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPENIGMA v1.2 specifies PM6 is not applicable for BRCA1/2: BRCA1/2-related cancers are relatively common and there is no information to calibrate the predictive capacity of de novo occurrences. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPPP2 is not applicable per ENIGMA v1.2. This criterion is excluded from the BRCA1/2 specification. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AENIGMA PP3 applies to (a) missense/in-frame variants inside a clinically important functional domain with BayesDel≥0.28, or (b) variants with predicted splicing impact (SpliceAI≥0.2). This is a frameshift variant; SpliceAI max delta score is 0.15 (<0.2 threshold). PP3 is not applicable to frameshift null variants per the ENIGMA bioinformatic code flowchart (Figure 1A). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score: 0.15 (below 0.2 threshold for splicing-based PP3)
- Frameshift variant — outside PP3 application scope per ENIGMA Figure 1A
Sources
PP5 VCEPPP5 is not for use per ENIGMA v1.2; excluded by ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
No further detail was recorded.
BS3 N/AENIGMA BS3 functional assay assessments (Table 9) apply to missense and synonymous variants only. This is a frameshift null variant; functional evidence is captured through the PVS1 framework. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AENIGMA BP1_Strong applies to silent substitutions, missense, or in-frame insertion/deletion/delins variants outside clinically important functional domains with SpliceAI≤0.1. This is an out-of-frame (frameshift) deletion and does not qualify under the BP1 rule. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPBP2 is not applicable per ENIGMA v1.2; BP2 is applied only in the context of BS2 and is not independently assigned. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPBP3 is not applicable per ENIGMA v1.2; in-frame deletions/insertions in repetitive regions are captured by the broader bioinformatic prediction and domain analysis framework. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel≤0.15 AND SpliceAI≤0.1, or to silent/intronic variants with SpliceAI≤0.1. This is a frameshift null variant and does not meet the variant-type requirements for BP4. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is not for use per ENIGMA v1.2; excluded by ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AENIGMA BP7 applies to silent and intronic variants, as well as missense/in-frame variants for RNA-level splicing assays. This is a frameshift null variant and does not fall within BP7 scope under the ENIGMA specification (Figure 1B). Details ▾Hide ▴
No further detail was recorded.
PS5 N/APP5 is not for use per the ClinGen Sequence Variant Interpretation VCEP Review Committee; excluded from the ENIGMA BRCA1/2 specification. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRCA1
- Transcript
- NM_007294.4
- Coding (HGVS c.)
- NM_007294.4:c.738del
- Protein (HGVS p.)
- NP_009225.1:p.(Asn247ThrfsTer51)
- GRCh38
- chr17:43094792 TC>T
- GRCh37
- chr17:41246809 TC>T
- ClinVar
- 3677163, 3254408, 2746628, 480990, 230126, 125465
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
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/AENIGMA PP3 applies to (a) missense/in-frame variants inside a clinically important functional domain with BayesDel≥0.28, or (b) variants with predicted splicing impact (SpliceAI≥0.2). This is a frameshift variant; SpliceAI max delta score is 0.15 (<0.2 threshold). PP3 is not applicable to frameshift null variants per the ENIGMA bioinformatic code flowchart (Figure 1A). Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score: 0.15 (below 0.2 threshold for splicing-based PP3)
- Frameshift variant — outside PP3 application scope per ENIGMA Figure 1A
Sources
BP4 N/AENIGMA BP4 applies to missense or in-frame variants inside clinically important functional domains with BayesDel≤0.15 AND SpliceAI≤0.1, or to silent/intronic variants with SpliceAI≤0.1. This is a frameshift null variant and does not meet the variant-type requirements for BP4. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AENIGMA BP7 applies to silent and intronic variants, as well as missense/in-frame variants for RNA-level splicing assays. This is a frameshift null variant and does not fall within BP7 scope under the ENIGMA specification (Figure 1B). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).
8 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 11358863 ↗Tumorigenesis in mice carrying a truncating Brca1 mutation.Reports generation and characterization of Brca1(tr/tr) mice carrying a C-terminal truncation that eliminates the BRCT domain. The murine model is a gene-level experimental construct, not NM_007294.4:c.738del.Does not name this variant
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PMID 12483515 ↗The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans.Review article discussing BRCA1 and BRCA2 tumor suppression models in mice and humans, covering knockout and truncation models at the gene level.Does not name this variant
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PMID 12947386 ↗Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation.Review describing BRCA1 and BRCA2 roles in homologous recombination, DNA replication fidelity, and cellular response to ionizing radiation at the gene/protein level.Does not name this variant
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PMID 20608970 ↗BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications.Review summarizing risk-associated BRCA1 mutations and their functional implications, discussing domain-specific effects of mutations across BRCA1.Does not name this variant
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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 (ASCO) policy statement on genetic testing for cancer susceptibility. Provides recommendations for clinical practice, not variant-level 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. · 2010Updated ASCO policy statement on genetic and genomic testing for cancer susceptibility. A practice guideline with no variant-specific data.Does not name this variant
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993GeneReviews clinical summary for BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. Provides gene-level overview of hereditary cancer syndrome.Does not name this variant
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PMID 23188549 ↗NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.National Society of Genetic Counselors (NSGC) practice guideline for risk assessment and genetic counseling for hereditary breast and ovarian cancer. Professional guideline with no variant-level evidence.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 0.150
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/?term=NM_007294.4%3Ac.738del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-41246809-TC-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-43094792-TC-T?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-43094792-TC-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007294.4%3Ac.738d…
- OncoKB ↗www.oncokb.org/gene/BRCA1/N247Tfs*51
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRCA1+c.738del
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.