Variant classification summary

NM_000059.4:c.2164A>T

BRCA2 · NP_000050.3:p.(Lys722Ter) · NM_000059.4

GRCh37: chr13:32910656 A>T · GRCh38: chr13:32336519 A>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

PVS1 very strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Lys722Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): c.2164A>T creates the premature termination codon p.(Lys722Ter) in BRCA2 exon 11, predicted to trigger nonsense-mediated decay.

2

Final classification: Uncertain Significance — PVS1 (Very Strong) alone is met, and the ENIGMA VCEP rule requires additional Strong, Moderate, or two Supporting criteria for a pathogenic call.

Final determination: A lone Very Strong (PVS1) without an accompanying Strong/Moderate/2xSupporting pathogenic criterion does not meet any ENIGMA Table 3 P/LP combination, and no benign criteria are met, so the call is 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 (Very Strong): this nonsense change creates p.(Lys722Ter) in exon 11, predicted to trigger nonsense-mediated decay.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 pvs1_generic_framework
PS1	N/A	Not applicable: PS1 requires a missense or splice-altering variant, and this nonsense change has no splice impact (SpliceAI max delta 0.005).	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA specification excludes de novo-based PS2 for BRCA2-related cancers.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay result for p.(Lys722Ter) was available.
PS4	Not assessed	Not assessed: no case-control enrichment data exist for this variant.	cspec vcep_humu_40_1557_s001
PM1	N/A	Not applicable: the ENIGMA BRCA2 specification designates PM1 as not applicable for this gene.	cspec
PM2	Not assessed	Not assessed: the variant is absent from gnomAD v2.1, but the required average read depth of at least 25 was not reported.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype, second pathogenic BRCA2 variant, or phase information was available.	cspec
PM4	N/A	Not applicable: PM4 covers in-frame indels and stop-loss changes, not this nonsense variant already counted under PVS1.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: no previously classified pathogenic exon-11 premature termination codon variant was identified as a comparator.	vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates cspec
PM6	N/A	Not applicable: the ENIGMA specification excludes de novo-based PM6 for BRCA2-related cancers.	cspec
PP1	Not assessed	Not assessed: no quantitative co-segregation data were available (LR of at least 2.08:1 required).	cspec
PP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.01 is below the 0.2 threshold for predicted splice impact.	cspec spliceai
PP4	Not assessed	Not assessed: no clinical-history likelihood ratio is available for this variant.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
PP5	N/A	Not applicable: not used in the ENIGMA BRCA2 specification, and no expert-panel ClinVar assertion exists for this variant.	cspec clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency above the 0.1% threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: absent from gnomAD, with no allele frequency above the 0.002% BS1_Supporting threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygous carriers or carrier phenotype data were available.	cspec
BS3	N/A	Not applicable: BS3 requires functional evidence of no damaging effect, which does not apply to this truncating nonsense variant.
BS4	Not assessed	Not assessed: no co-segregation data demonstrating lack of segregation were available (LR of 0.48:1 or lower required).	cspec
BP1	N/A	Not applicable: BP1 covers silent, missense, or in-frame changes, not nonsense variants.	cspec
BP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP3 as not applicable.	cspec
BP4	Not met	Not met: BP4 is scoped to missense, silent, or intronic variants, and this is a nonsense change (SpliceAI max delta 0.01).	cspec spliceai
BP5	Not assessed	Not assessed: no clinical-history likelihood ratio is available for this variant.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
BP6	N/A	Not applicable: not used in the ENIGMA BRCA2 specification, and no expert-panel ClinVar assertion exists for this variant.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this is a nonsense change.

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.