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NM_007294.4:c.1387A>T
p.Lys463Ter · BRCA1
0%
complete
Final classification
Likely Pathogenic
PVS1PM2
BRCA1
c.1387A>T
p.Lys463Ter
nonsense · exon 10

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

This variant

BRCA1 is a tumor suppressor essential for DNA double-strand break repair, and loss-of-function variants are the established mechanism behind hereditary breast and ovarian cancer risk. This variant creates a premature stop codon predicted to eliminate functional protein through nonsense-mediated decay, consistent with that established disease mechanism, and its complete absence from population databases further supports pathogenic potential, together supporting a Likely Pathogenic classification.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.1387A>T
GRCh38
chr17:43094144 T>A
GRCh37
chr17:41246161 T>A
Likely Pathogenic from two applicable criteria: PVS1 (Very Strong, predicted nonsense-mediated decay) and PM2 (Supporting, absent from population databases).
Classification rationale
PVS1PM2 Likely Pathogenic
BRCA1 c.1387A>T nonsense · exon 10

PVS1 (Very Strong): nonsense change p.(Lys463Ter) predicted to trigger nonsense-mediated decay. PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. Overall: Likely Pathogenic, based on combining one Very Strong and one Supporting criterion per ENIGMA BRCA1/BRCA2 rules.

PVS1 + PM2 → Likely Pathogenic
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.
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PVS1 very strong Pathogenic
Met (Very Strong): this nonsense change creates a premature stop, p.(Lys463Ter), predicted to trigger nonsense-mediated decay well upstream of the final exon.
case_summary.json cspec block: PVS1 defaultStrength 'Pathogenic Very Strong'; rule text: 'Null variant (nonsense, frameshift, splice site...) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart... See Specifications Table 4 and Appendix D for details.'pvs1_gene_context.json: gene=BRCA1, germline_disease_context_found=true, lof_mechanism_supported=true, pvs1_gene_gate='eligible', mechanism_rationale citing official CSPEC/VCEP PVS1 guidance for BRCA1.pvs1_variant_assessment.json: consequence_class='nonsense', variant_bucket='nonsense', suggested_default_strength='PVS1', protein change NP_009225.1:p.(Lys463Ter).
PM2 supporting review Pathogenic
Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.
gnomAD v2.1 (exome, non-cancer subset) search for 17-41246161-T-A returned absent, found=false.gnomAD v4.1 search for chr17-43094144-T-A returned absent, found=false.gnomAD-Canada v1.0 (HostSeq genomes) API query for 17-43094144-T-A returned absent, found=false.
Assessed · not applied · 2 not met · 12 not assessed
Pathogenic
PS1 Not assessed: insufficient evidence was available to evaluate this criterion.
PS4 Not assessed: no case-control enrichment or odds-ratio data for this exact variant were available.
PM1 Not assessed: insufficient evidence was available to evaluate this criterion.
PM3 Not assessed: no proband case report or phasing data linking this variant to a second pathogenic variant were available.
PM5 Not assessed: insufficient evidence was available to evaluate this criterion.
PP1 Not assessed: no family segregation or pedigree data for this variant were available.
PP2 Not assessed: insufficient evidence was available to evaluate this criterion.
PP4 Not assessed: no variant-specific clinical or family-history likelihood-ratio data were available.
Benign
BA1 Not met: the variant is completely absent from population databases, far below the >0.1% frequency threshold.
BS1 Not met: the variant is absent from population databases, well below the >0.01% frequency threshold.
BS2 Not assessed: no carrier phenotype or zygosity data were available to evaluate this criterion.
BS4 Not assessed: no family segregation data showing non-segregation were available.
BP1 Not assessed: insufficient evidence was available to evaluate this criterion.
BP5 Not assessed: no variant-specific clinical-history likelihood-ratio data were available.
N/A · 12 PS2 · PS3 · PM4 · PM6 · PP3 · PP5 · BS3 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.60222.
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
11358863 ↗ Tumorigenesis in mice carrying a truncating Brca1 mutation. ONCOKB
12483515 ↗ The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. ONCOKB
12947386 ↗ Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. ONCOKB
20608970 ↗ BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications. ONCOKB
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
24432435 ↗ PMID 24432435 CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR