Variant classification summary

NM_000059.4:c.7484T>C

BRCA2 · NP_000050.3:p.(Ile2495Thr) · NM_000059.4

GRCh37: chr13:32930613 T>C · GRCh38: chr13:32356476 T>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BS3 strong PP3 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile2495Thr)

gnomAD AF

2.416228131586545e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS3 Strong is assigned from two calibrated neutral functional studies.

2

PP3 Supporting: REVEL 0.663 exceeds the 0.644 supporting threshold.

3

Likely Benign: ENIGMA's conflicting-evidence score is −3 (BS3 −4 plus PP3 +1).

Final determination: Under the ENIGMA v1.2 conflicting-evidence point system, BS3 Strong (−4) plus PP3 Supporting (+1) yields −3, which maps to Likely Benign (−6 to −2).

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	N/A	Not applicable: p.(Ile2495Thr) is a missense variant, whereas ENIGMA PVS1 is restricted to specified null variants and canonical splice changes.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1	Not met	Not met: no qualifying pathogenic variant producing the same Ile2495Thr amino-acid change was identified in the governing VCEP materials.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS2	N/A	Not applicable: ENIGMA explicitly prohibits PS2 for BRCA1/2-related cancers because de novo predictive capacity is uncalibrated.	cspec
PS3	Not met	Not met: ENIGMA Table 9 assigns BS3 Strong after two calibrated studies found no damaging effect, including 58% HDR and 84% cisplatin sensitivity in Mesman et al.	cspec PMID:29988080
PS4	Not assessed	Not assessed: the exact variant row lacks a qualifying PS4 case-control OR and p-value, and ENIGMA prohibits using its two observations as proband-counting evidence.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	Not applicable: Ile2495 lies in the DNA-binding domain, but ENIGMA V1.2 explicitly prohibits PM1 and routes domain evidence to bioinformatic analysis.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Not met	Not met: the variant is observed in both required non-cancer datasets, with 2 alleles in v2.1 exomes and 1 allele in v3.1 genomes.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented Fanconi anemia phenotype, qualifying BRCA2 co-occurring pathogenic variant, or phase information supports ENIGMA PM3 points.	cspec
PM4	N/A	Not applicable: p.(Ile2495Thr) changes one amino acid without altering protein length, and ENIGMA explicitly instructs that PM4 is not used.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM5	N/A	Not applicable: c.7484T>C is missense, while ENIGMA reserves PM5 for protein-termination-codon logic and does not use classic missense PM5.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	Not applicable: ENIGMA explicitly prohibits PM6 because de novo predictive capacity for BRCA1/2-related cancers is uncalibrated.	cspec
PP1	Not assessed	Not assessed: the exact variant row has no segregation LR, and no quantitative co-segregation result or meiosis count is available for comparison with PP1 LR ≥2.08.	cspec vcep_humu_40_1557_s001
PP2	N/A	Not applicable: ENIGMA V1.2 explicitly prohibits PP2 for BRCA2 because benign missense variation is frequent.	cspec vcep_specifications_v1_2_2024_11_18
PP3	Met	Met, Supporting: REVEL 0.663 meets the ClinGen SVI PP3 supporting threshold of 0.644 for missense variants.	cspec revel vcep_supplementarytables_v1_2_2024_11_18
PP4	N/A	Not applicable: combined LR 0.7333055058687654 >= 2.08? no, so it does not reach ENIGMA's PP4 Supporting threshold.	cspec vcep_humu_40_1557_s001
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel classification; its available submissions are single-laboratory assertions, not eligible PP5 evidence.	clinvar cspec
BA1	Not met	Not met: maximum required non-cancer filter allele frequency was 3.23e-06, below the ENIGMA BA1 threshold of >0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum required non-cancer filter allele frequency was 3.23e-06, below the ENIGMA BS1 Supporting threshold of >0.00002.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no qualifying phenotyped healthy-adult or clinical-cohort BS2 observations are available.	cspec gnomad_v2 gnomad_v4
BS3	Met	Met, Strong: ENIGMA Table 9 assigns BS3 Strong from two calibrated neutral studies, including Mesman results of 58% HDR and 84% cisplatin sensitivity versus wild type.	cspec PMID:29988080
BS4	Not assessed	Not assessed: the exact variant row has no segregation LR, and the available combined LR 0.7333 is above the BS4 supporting threshold of ≤0.48.	cspec vcep_humu_40_1557_s001
BP1	Not met	Not met: Ile2495 lies inside the ENIGMA DNA-binding domain 2481-3186, whereas BP1 requires a missense variant outside a clinically important domain.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BP2	N/A	Not applicable: the ENIGMA BRCA2 VCEP prohibits BP2 and permits it only in the context of BS2.	cspec
BP3	N/A	Not applicable: p.(Ile2495Thr) is a missense substitution, while ENIGMA BP3 is restricted to in-frame indels in repetitive regions without known function and is not used.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
BP4	Not met	Not met: REVEL 0.663 exceeds the ClinGen SVI BP4 supporting threshold of <=0.29 for missense variants.	cspec revel spliceai
BP5	N/A	Not applicable: combined LR 0.7333055058687654 <= 0.48? no, placing it in ENIGMA's neutral BP5 interval.	cspec vcep_humu_40_1557_s001
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel classification; its available Likely benign submissions are ordinary laboratory assertions and cannot trigger BP6.	clinvar cspec
BP7	N/A	Not applicable: c.7484T>C is missense, whereas BP7 is restricted to synonymous or qualifying intronic variants.	cspec

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