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

VUS

PVS1 very strong

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 p.(Lys463Ter) in the large exon E10(11) is predicted to trigger nonsense-mediated decay, consistent with the established BRCA1 loss-of-function disease mechanism.

2

Overall: VUS, because the sole PVS1 (Very Strong) criterion satisfies no Pathogenic or Likely Pathogenic combination under the ENIGMA Table 3 framework.

Final determination: ENIGMA Table 3 requires PVS1 Very Strong plus at least one Supporting criterion for Likely Pathogenic; PVS1 Very Strong alone therefore remains Uncertain Significance.

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 at Very Strong: nonsense p.(Lys463Ter) in the large exon E10(11) is predicted to trigger nonsense-mediated decay.	cspec vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	Not applicable: PS1 covers missense substitutions or matched splicing effects, not this nonsense p.(Lys463Ter) change.	cspec
PS2	N/A	Not applicable: ENIGMA excludes PS2 for BRCA1/2 because the predictive capacity of de novo occurrences is uncalibrated.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result for c.1387A>T or p.(Lys463Ter) was available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no case-control dataset reporting c.1387A>T prevalence in affected individuals and controls was available.	cspec
PM1	N/A	Not applicable: ENIGMA folds PM1 into bioinformatic analysis, and residue 463 lies outside the BRCA1 critical domains.	cspec vcep_appendices_v1_2_2024_11_18
PM2	Not assessed	Not assessed: variant is absent from gnomAD v2.1 and v4.1, but the required average regional read depth (>=25) was unavailable.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no Fanconi-anemia phenotype, second BRCA1 variant, or phase information establishing trans configuration was available.	cspec gnomad_v2 gnomad_v4
PM4	N/A	Not applicable: ENIGMA excludes PM4, and this is a nonsense substitution, not an in-frame insertion/deletion or stop-loss.	cspec
PM5	Not assessed	Not assessed: no proven pathogenic premature-termination-codon variant in exon 10 was identified as a comparator.	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	Not applicable: ENIGMA excludes PM6 for BRCA1/2 for the same uncalibrated de novo evidence reason as PS2.	cspec
PP1	Not assessed	Not assessed: no affected-relative genotypes or segregation likelihood ratio was available.	cspec
PP2	N/A	Not applicable: PP2 is a missense-gene-level criterion, and this variant is a nonsense substitution.	cspec
PP3	N/A	Not applicable: PP3 excludes nonsense variants, and the SpliceAI maximum delta of 0.001 is below the 0.2 threshold.	cspec spliceai
PP4	Not assessed	Not assessed: no c.1387A>T clinical-history likelihood ratio was present in the ENIGMA table.	cspec vcep_pmid_31853058_brca1_clinical_history_lr
PP5	Not assessed	Not assessed: no ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: variant absent from gnomAD v2.1 and v4.1, so no allele frequency above the 0.1% BA1 threshold is observed.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: variant absent from gnomAD v2.1 and v4.1, so no allele frequency above the BS1 threshold of 0.0001 is observed.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrier, homozygote observation, or recessive-disease exclusion data was available.	cspec
BS3	Not assessed	Not assessed: no variant-specific functional assay showing preserved protein function was available.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no affected-relative genotypes or segregation likelihood ratio was available.	cspec
BP1	N/A	Not applicable: BP1 covers silent, missense, or in-frame variants, not this nonsense p.(Lys463Ter) change.	cspec
BP2	N/A	Not applicable: ENIGMA applies BP2 only in the context of BS2.	cspec
BP3	N/A	Not applicable: BP3 covers in-frame indels in repetitive regions, not this nonsense substitution.	cspec
BP4	N/A	Not applicable: BP4 excludes nonsense variants; the SpliceAI score of 0.001 does not make this truncating variant eligible.	cspec spliceai
BP5	Not assessed	Not assessed: no c.1387A>T clinical-history likelihood ratio was present in the ENIGMA table.	cspec vcep_pmid_31853058_brca1_clinical_history_lr
BP6	Not assessed	Not assessed: no ClinVar expert-panel Benign or Likely benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 excludes nonsense variants, and no variant-specific normal mRNA assay was provided.	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.