Variant classification summary

NM_000059.4:c.9738C>T

BRCA2 · NP_000050.3:p.(Ala3246=) · NM_000059.4

GRCh37: chr13:32972388 C>T · GRCh38: chr13:32398251 C>T

Gene: BRCA2 Transcript: NM_000059.4

Final call

Benign

BA1 stand-alone benign BS1 strong BP1 strong BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ala3246=)

gnomAD AF

5.5145099769258035e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 is met by the gnomAD v2.1 non-cancer exome maximum filter allele frequency of 0.00142293, above 0.001.

2

Benign: BS1 strong is met because the maximum filter allele frequency of 0.00142293 exceeds 0.0001.

3

Benign: BP1 strong is met for the synonymous Ala3246 change outside the clinically important domains without predicted splice impact.

4

Benign: BP4 supporting is met because SpliceAI maximum delta is 0.013, below 0.1.

5

Benign: BP6 supporting is met by the exact-variant ClinVar expert-panel Benign classification.

6

Benign: BP7 supporting is met because the synonymous variant satisfies the BP4 no-splice-impact prerequisite.

Final determination: Under the ClinGen ENIGMA BRCA2 Version 1.2 Table 3 framework, one met BA1 stand-alone benign criterion is sufficient for a Benign 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	N/A	Not applicable: c.9738C>T is synonymous (p.Ala3246=), with SpliceAI max delta 0.013 and no qualifying loss-of-function consequence.	vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:12442275
PS1	N/A	Not applicable: the synonymous p.Ala3246= change is neither a missense match nor a demonstrated pathogenic splice-event match, with SpliceAI max delta 0.013.	vcep_specifications_v1_2_2024_11_18 spliceai
PS2	N/A	Not applicable: the ENIGMA VCEP explicitly prohibits PS2 because de novo predictive capacity is uncalibrated for BRCA1/2-related cancers.	vcep_specifications_v1_2_2024_11_18
PS3	Not assessed	Not assessed: no calibrated protein-function or combined mRNA-and-protein assay entry was found for c.9738C>T (p.Ala3246=).	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not met	Not met: published observations lack the ENIGMA PS4 requirements of p-value <=0.05, OR >=4, and a confidence interval excluding 2.0.	vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:12442275 PMID:15889636
PM1	N/A	Not applicable: Ala3246 lies outside the ENIGMA BRCA2 critical domains, which end at residue 3186, and the variant is synonymous.	vcep_specifications_v1_2_2024_11_18
PM2	Not met	Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 0.0002660855 and gnomAD v3.1 non-cancer genomes at AF 0.0000473491.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no documented Fanconi anemia phenotype, pathogenic BRCA2 co-occurring variant, phase, or PM3-scoring affected-proband observation is available.	vcep_specifications_v1_2_2024_11_18
PM4	N/A	Not applicable: p.Ala3246= causes no protein-length change, and ENIGMA explicitly designates PM4 as not applicable.	vcep_specifications_v1_2_2024_11_18
PM5	N/A	Not applicable: ENIGMA PM5 is restricted to PTC/truncating variants, whereas c.9738C>T is synonymous and yields p.Ala3246=.	vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA VCEP explicitly prohibits PM6 because de novo predictive capacity is uncalibrated for BRCA1/2-related cancers.	vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	Not assessed: no pedigree or quantitative co-segregation likelihood ratio is available to compare with the ENIGMA PP1 thresholds of 2.08, 4.3, 18.7, or 350.	vcep_specifications_v1_2_2024_11_18 PMID:12442275 PMID:15889636 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PP2	N/A	Not applicable: the governing ENIGMA BRCA2 framework marks PP2 not applicable, and this variant is synonymous rather than missense.	vcep_specifications_v1_2_2024_11_18
PP3	Not met	Not met: SpliceAI maximum delta 0.013 is below the ENIGMA PP3 threshold of >=0.2 for predicted splicing in silent variants.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
PP4	Not assessed	Not assessed: no exact-variant combined clinical likelihood ratio was available for comparison with the PP4 threshold of LR >=2.08.	vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 PMID:31853058 PMID:17924331
PP5	Not met	Not met: exact-variant ClinVar expert-panel classification is Benign, not Pathogenic or Likely pathogenic, so PP5 is not triggered.	clinvar vcep_specifications_v1_2_2024_11_18
BA1	Met	Met: gnomAD v2.1 non-cancer exome maximum filter allele frequency 0.00142293 exceeds the BRCA2 VCEP BA1 threshold of 0.001.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS1	Met	Met, strong: gnomAD v2.1 non-cancer exome maximum filter allele frequency 0.00142293 exceeds the BRCA2 VCEP BS1 threshold of 0.0001.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2
BS2	Not assessed	Not assessed: one gnomAD homozygote is frequency evidence, not the VCEP's required phenotyped healthy-adult observation for BS2.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no calibrated benign protein-function or combined mRNA-and-protein assay entry was found for c.9738C>T (p.Ala3246=).	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	Not assessed: no affected-relative non-segregation result or quantitative likelihood ratio is available to compare with the ENIGMA BS4 thresholds of 0.48, 0.23, 0.05, or 0.00285.	vcep_specifications_v1_2_2024_11_18 PMID:12442275 PMID:15889636 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	Met	Met, Strong: synonymous Ala3246 is outside the aa 2481-3186 DNA-binding domain and SpliceAI max delta 0.013 is below the <=0.1 threshold.	vcep_specifications_v1_2_2024_11_18 spliceai
BP2	N/A	Not applicable: the ENIGMA BRCA2 VCEP explicitly says BP2 is not used and is applied only in the context of BS2.	vcep_specifications_v1_2_2024_11_18
BP3	N/A	Not applicable: c.9738C>T is a synonymous single-nucleotide substitution, not an in-frame insertion or deletion in a repeat region.	vcep_specifications_v1_2_2024_11_18
BP4	Met	Met, Supporting: SpliceAI maximum delta 0.013 meets the ENIGMA BP4 threshold of <=0.1 for no predicted splice impact.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai
BP5	Not assessed	Not assessed: no exact-variant combined LR was available for comparison with the BP5 Supporting threshold of LR <=0.48.	vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 PMID:31853058 PMID:17924331
BP6	Met	Met, Supporting: exact-variant ClinVar expert-panel classification is Benign for c.9738C>T (p.Ala3246=), satisfying the requested BP6 rule.	clinvar
BP7	Met	Met, Supporting: synonymous p.Ala3246= has SpliceAI maximum delta 0.013, satisfying BP4 and the ENIGMA BP7 requirement for silent variants.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai

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