Variant classification summary

NM_000059.4:c.8275del

BRCA2 · NP_000050.3:p.(Val2759TrpfsTer18) · NM_000059.4

GRCh37: chr13:32937612 TG>T · GRCh38: chr13:32363475 TG>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM5 strong

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Val2759TrpfsTer18)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): exon 18 frameshift creates premature stop p.(Val2759TrpfsTer18), a truncating change in a gene where loss of function causes disease.

2

PM5 (Strong): other expert-panel-reviewed pathogenic premature-stop variants are documented in the same exon, adding strong weight under the ENIGMA PM5_PTC rule.

3

Overall: Pathogenic, from PVS1 (Very Strong) plus PM5 (Strong) meeting the ENIGMA BRCA2 v1.2 combination rule.

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, one Very Strong pathogenic criterion plus at least one Strong pathogenic criterion yields a Pathogenic classification.

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: this exon 18 frameshift creates premature stop p.(Val2759TrpfsTer18), and the ENIGMA v1.2 exon-level table assigns PVS1 to such exon 18 truncations.	cspec vcep_specifications_table4_v1_2_2024_11_18 PMID:10570174
PS1	N/A	Not applicable: this is a frameshift premature-stop variant, not a missense, and its SpliceAI max delta of 0.095 indicates no significant splice effect.	cspec spliceai
PS2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification does not apply PS2, so de novo evidence is not adjudicated for this disorder.	cspec
PS3	Not assessed	Not assessed: no validated functional assay evidence specific to this variant was available; existing functional studies concern other BRCA2 variants.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
PS4	Not assessed	Not assessed: no matched case-control data for this variant were available, and ENIGMA requires a case-control p-value of 0.05 or less with an odds ratio of 4 or more.	cspec
PM1	N/A	Not applicable: PM1 is restricted to missense or in-frame variants in critical domains; this frameshift premature truncation is not eligible.	cspec vcep_appendices_v1_2_2024_11_18
PM2	N/A	Not applicable: the ENIGMA specification excludes deletion variants from PM2 even though this variant is absent from gnomAD v2.1 and v4.1.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no Fanconi anemia phenotype, second BRCA2 variant, or phase information was available to support PM3.	cspec
PM4	N/A	Not applicable: PM4 concerns in-frame protein-length or stop-loss changes; this frameshift is scored under the PVS1 framework instead.	cspec vcep_specifications_v1_2_2024_11_18
PM5	Met	Met at Strong: the ENIGMA table assigns PM5_Strong to exon 18 premature-stop variants, with other pathogenic truncations such as p.Lys2715Ter documented in the same exon.	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates clinvar
PM6	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification does not apply PM6, so presumed de novo evidence is not adjudicated.	cspec
PP1	Not assessed	Not assessed: no pedigree or quantitative co-segregation data for this variant were available, so no PP1 strength could be assigned.	cspec
PP2	N/A	Not applicable: ENIGMA does not apply PP2 for BRCA2, and this frameshift is not a missense variant eligible for missense-enrichment evidence.	cspec
PP3	N/A	Not applicable: PP3 is restricted to non-frameshift variant classes, and the SpliceAI max delta of 0.095 is below the 0.20 splice-impact threshold.	cspec spliceai
PP4	Not assessed	Not assessed: no combined multifactorial clinical likelihood ratio for this variant was supplied, which ENIGMA requires for PP4 in BRCA2.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Not met	Not met: no ClinVar record for this exact variant was found, so no expert-panel pathogenic assertion could be cited.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no allele frequency above the 0.1% BA1 threshold is demonstrated.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no frequency above the BS1 thresholds (0.01% strong, 0.002% supporting) is demonstrated.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carriers or genotype-phenotype observations for this variant were available to score BS2.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay demonstrating a benign (no damaging effect) outcome for this specific variant was identified.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 PMID:10570174 PMID:11239455 PMID:20878484 PMID:22193408 PMID:24312913
BS4	Not assessed	Not assessed: no pedigree or segregation data were available to demonstrate lack of segregation with disease.	cspec
BP1	N/A	Not applicable: BP1 is limited to silent, missense, or in-frame variants; this frameshift premature-stop variant is outside its scope.	cspec spliceai
BP2	N/A	Not applicable: the ENIGMA specification designates BP2 as not applicable for BRCA2.	cspec
BP3	N/A	Not applicable: BP3 concerns in-frame length changes in repetitive regions; this frameshift premature-stop variant does not qualify.	cspec
BP4	N/A	Not applicable: BP4 is restricted to missense, in-frame, silent, or intronic variants; this frameshift is ineligible despite its low SpliceAI score.	cspec spliceai
BP5	Not assessed	Not assessed: no combined clinical likelihood ratio against pathogenicity was supplied, which ENIGMA requires for BP5 in BRCA2.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	Not met	Not met: no ClinVar record for this exact variant was found, so no expert-panel benign assertion could be cited.	clinvar
BP7	N/A	Not applicable: BP7 applies to silent or intronic variants, and no mRNA assay demonstrating no damaging effect exists for this frameshift.	cspec spliceai

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