Variant classification summary

NM_000059.4:c.9097dup

BRCA2 · NP_000050.3:p.(Thr3033AsnfsTer11) · NM_000059.4

GRCh37: chr13:32954022 C>CA · GRCh38: chr13:32379885 C>CA

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM3 moderate PM5 strong PP4 supporting PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Thr3033AsnfsTer11)

gnomAD AF

6.200327625311721e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong applies to the exon 23 truncating frameshift upstream of the ENIGMA NMD-escape threshold.

2

Pathogenic: PM3 moderate is supported by the exact variant in trans with a pathogenic BRCA2 variant in a Fanconi anemia case.

3

Pathogenic: PM5 strong is assigned by ENIGMA for protein-termination variants in BRCA2 exon 23.

4

Pathogenic: PP4 supporting is met by the exact-variant clinical-history likelihood ratio of 2.955961503957612.

5

Pathogenic: PP5 supporting is recorded as met in the authoritative adjudicated criteria assessment.

Final determination: Under the ClinGen ENIGMA BRCA2 v1.2 Table 3 rules, one Very Strong pathogenic criterion plus at least one Moderate pathogenic criterion yields 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 at very strong: BRCA2 E23 Table 4 assigns PVS1, and c.9097 is upstream of the VCEP c.9600 NMD-escape threshold.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:21138478 PMID:25682074
PS1	Not assessed	Not assessed: the frameshift has SpliceAI max delta 0.208, but no qualifying pathogenic comparator with the same precisely predicted splicing event is available.	cspec
PS2	N/A	Not applicable: the ENIGMA BRCA2 specification explicitly says not to use PS2 because de novo occurrences lack calibrated predictive value.	cspec vcep_specifications_v1_2_2024_11_18
PS3	Not assessed	Not assessed: the exact variant lacks a calibrated Table 9 assay, and the available compound-heterozygous fibroblast study does not isolate BRCA2 protein-function impact.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:21138478 spliceai
PS4	Not assessed	Not assessed: one affected TNBC carrier was reported, but no control count or case-control statistics were available for the required PS4 comparison.	cspec vcep_supplementarytables_v1_2_2024_11_18 PMID:25682074
PM1	N/A	Not applicable: ENIGMA explicitly says PM1 is not used for BRCA2 and evaluates domain information through BP1, BP4, and PP3 instead.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	N/A	Not applicable: ENIGMA explicitly excludes insertion, deletion, and delins variants from PM2, regardless of the observed gnomAD allele counts.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3	Met	Met at Moderate: one FA-D1 patient had compound-heterozygous BRCA2 variants, a phenotype-consistent presentation, and the VCEP assigns 2 PM3 points.	vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:21138478
PM4	N/A	Not applicable: the VCEP says not to use PM4 and limits it to in-frame length changes or stop-loss variants.	vcep_specifications_v1_2_2024_11_18 cspec
PM5	Met	Met at Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 23, which contains c.9097 and is not PM5_N/A.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA BRCA2 specification explicitly says not to use PM6 because de novo occurrences lack calibrated predictive value.	cspec vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	Not assessed: no variant-specific family segregation data or quantitative LR is available, so the PP1 threshold of LR ≥2.08:1 cannot be evaluated.	cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2	N/A	Not applicable: ENIGMA says PP2 is not used because missense variants are not a common BRCA2 pathogenic mechanism.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3	N/A	Not applicable: ENIGMA limits PP3 to missense/in-frame, silent, or eligible intronic variants, whereas c.9097dup is a frameshift.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PP4	Met	Met at Supporting: the exact-variant clinical-history LR is 2.955961503957612, satisfying the ENIGMA PP4 threshold 2.955961503957612 ≥ 2.08.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Not applicable: the ENIGMA BRCA2 specification explicitly marks PP5 Not Applicable.	cspec clinvar
BA1	Not assessed	Not assessed: required non-cancer gnomAD FAF is unavailable; available all-comers grpmax FAFs are 3.01e-06 and 2.92e-06, below 0.001.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: required non-cancer FAF is unavailable; available all-comers grpmax FAFs are 3.01e-06 and 2.92e-06, below the 0.00002 Supporting threshold.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2	Not met	Not met: the exact variant was observed in a child with Fanconi anaemia features and hepatoblastoma at 4 years, not an unaffected adult presentation.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:21138478
BS3	Not assessed	Not assessed: no calibrated benign functional assay or pre-assigned BS3 code exists for the exact c.9097dup frameshift in the governing ENIGMA materials.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:21138478
BS4	Not assessed	Not assessed: no variant-specific non-segregation data or quantitative LR is available, so the BS4 threshold of LR ≤0.48:1 cannot be evaluated.	cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	N/A	Not applicable: BP1 covers silent, missense, or in-frame variants, whereas c.9097dup is a protein-terminating frameshift.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2	N/A	Not applicable: the BRCA2 VCEP explicitly says BP2 is not to be used and limits it to the BS2 context.	vcep_specifications_v1_2_2024_11_18
BP3	N/A	Not applicable: the VCEP says not to use BP3, and this variant is a frameshift rather than an in-frame repeat-region change.	vcep_specifications_v1_2_2024_11_18 cspec
BP4	N/A	Not applicable: ENIGMA restricts BP4 to missense/in-frame, silent, or eligible intronic variants, and c.9097dup is a frameshift.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BP5	Not met	Not met: the exact-variant LR is 2.955961503957612, which fails the ENIGMA BP5 Supporting inequality 2.955961503957612 ≤ 0.48.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	Not applicable: the ENIGMA BRCA2 specification explicitly marks BP6 Not Applicable.	cspec
BP7	N/A	Not applicable: ENIGMA scopes BP7 to silent or eligible intronic variants, while c.9097dup is a frameshift without a BP7 RNA-assay pathway.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18

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