Variant classification summary

NM_007294.4:c.1387A>T

BRCA1 · NP_009225.1:p.(Lys463Ter) · NM_007294.4

GRCh37: chr17:41246161 T>A · GRCh38: chr17:43094144 T>A

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Lys463Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense change p.(Lys463Ter) predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

3

Overall: Likely Pathogenic, based on combining one Very Strong and one Supporting criterion per ENIGMA BRCA1/BRCA2 rules.

Final determination: Per ENIGMA BRCA1/2 v1.2 Table 3, one Very Strong (PVS1) criterion plus one Supporting (PM2) criterion combine to Likely Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met (Very Strong): this nonsense change creates a premature stop, p.(Lys463Ter), predicted to trigger nonsense-mediated decay well upstream of the final exon.	cspec pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework vcep_specifications_table4_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PS2	N/A	Not applicable: BRCA1's expert panel excludes de novo evidence given the gene's reduced, age-dependent penetrance.	cspec
PS3	N/A	Not applicable: functional-assay evidence under this framework is restricted to missense and synonymous variants, not this nonsense change.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no case-control enrichment or odds-ratio data for this exact variant were available.	clinvar gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM2	Met	Met (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no proband case report or phasing data linking this variant to a second pathogenic variant were available.	cspec clinvar
PM4	N/A	Not applicable: this criterion covers in-frame length changes, not a nonsense substitution like this one.	cspec
PM5	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM6	N/A	Not applicable: BRCA1's expert panel excludes assumed de novo evidence for this reduced-penetrance cancer gene.	cspec
PP1	Not assessed	Not assessed: no family segregation or pedigree data for this variant were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PP3	N/A	Not applicable: bioinformatic prediction criteria apply only to missense, silent, or intronic variants, not this nonsense change.	cspec spliceai
PP4	Not assessed	Not assessed: no variant-specific clinical or family-history likelihood-ratio data were available.
PP5	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel classification exists to invoke.	clinvar cspec
BA1	Not met	Not met: the variant is completely absent from population databases, far below the >0.1% frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, well below the >0.01% frequency threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no carrier phenotype or zygosity data were available to evaluate this criterion.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	N/A	Not applicable: functional-assay evidence under this framework is restricted to missense and synonymous variants, not this nonsense change.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no family segregation data showing non-segregation were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP2	N/A	Not applicable: this criterion is excluded entirely under the BRCA1/BRCA2 expert-panel framework.	cspec
BP3	N/A	Not applicable: this criterion covers in-frame indels in repetitive regions, not a nonsense substitution like this one.	cspec
BP4	N/A	Not applicable: computational benign-prediction criteria apply only to missense, silent, or intronic variants, not this nonsense change.	cspec spliceai
BP5	Not assessed	Not assessed: no variant-specific clinical-history likelihood-ratio data were available.
BP6	N/A	Not applicable: the variant is absent from ClinVar, so no expert-panel benign classification exists to invoke.	clinvar cspec
BP7	N/A	Not applicable: this criterion covers silent or intronic variants, not this nonsense change.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.